Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].[NH3:15]>O1CCCC1>[F:8][C:7]1[C:6]([F:9])=[CH:5][C:4]([F:10])=[C:3]([C:11]([F:14])([F:13])[F:12])[C:2]=1[NH2:15]
Reactant: N
Reactant: Fc1cc(F)c(C(F)(F)F)c(F)c1F
Solvent: C1CCOC1
Product: Nc1c(F)c(F)cc(F)c1C(F)(F)F
Temperature: 100 °C

Procedure:
110 g of 2,3,4,6-tetrafluorobenzotrifluoride in 200 ml of tetrahydrofuran are initially introduced into a stainless steel autoclave of capacity 0.7 1, and 30 ml of liquid ammonia are injected. The batch is then heated at 100° C. for 3 hours (maximum pressure: 10 bar). After cooling, the pressure is released and the liquid phase is subjected to fractional distillation. First, at a boiling point of 47° C.-48° C./8 mbar, 42 g of 2,3,5-trifluoro-6-trifluoromethylaniline are obtained, and then, following an intermediate fraction and at a boiling point of 75° C.-78° C./ 8 mbar, 46 g of 2,3,5-trifluoro-4-trifluoromethylaniline.
Reaction SMILES: S1CCC(C2C([F:13])=CC(N3C[C@H](CN4C=C(C)N=N4)OC3=O)=CC=2F)CC1.Cl[C:29]1[CH:34]=CC=C(C(OO)=O)[CH:30]=1.[O:39]=[S:40]1(=[O:63])[CH2:45][CH:44]=[C:43]([C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][N:58]=[N+:59]=[N-:60])[O:54][C:53]3=[O:61])=[CH:48][C:47]=2[F:62])[CH2:42][CH2:41]1.CO>ClCCl>[O:63]=[S:40]1(=[O:39])[CH2:41][CH2:42][CH:43]([C:46]2[C:51]([F:13])=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][N:58]4[CH:30]=[C:29]([CH3:34])[N:60]=[N:59]4)[O:54][C:53]3=[O:61])=[CH:48][C:47]=2[F:62])[CH2:44][CH2:45]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)nn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5 [(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Example 24) (0.5 g, 1.27 mmol) was oxidized with 3-chloro perbenzoic acid (0.94 g, 3.8 mmol) as described for Intermediate 2. Chromatography on silica gel with 0-10% methanol in dichloromethane gave the title compound as as colourless solid (0.54 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[C:20]2[C:21]([C:26]3[CH:31]=[C:30]([C:32]([O:34]C)=O)[CH:29]=[C:28]([C:36]([OH:38])=[O:37])[CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.[CH3:39]N1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCC(N=C=N)C.[CH2:69]([NH2:73])[CH:70]([CH3:72])[CH3:71]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[C:20]2[C:21]([C:26]3[CH:31]=[C:30]([C:32]([NH:73][CH2:69][CH:70]([CH3:72])[CH3:71])=[O:34])[CH:29]=[C:28]([C:36]([O:38][CH3:39])=[O:37])[CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: CC(C)CN
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2ccccc2-c2cc(C(F)(F)F)ccc2OCc2ccc(F)cc2)c1
Agent: CC(CCCN(C)C)N=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)NCC(C)C)cc(-c2ccccc2-c2cc(C(F)(F)F)ccc2OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2″-{[(4-fluorophenyl)methyl]oxy}-5-[(methyloxy)carbonyl]-5″-(trifluoromethyl)-1,1′:2′,1″-terphenyl-3-carboxylic acid (90 mg, 0.17 mmol), 4-methylmorpholine (34 mg, 45 μl, 0.34 mmol), 1-hydroxybenzotriazole hydrate (30 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (38 mg, 0.2 mmol), and isobutylamine (25 mg, 34 ul, 0.34 mmol) in dichloromethane (3 ml) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (10 ml), then washed with saturated NaHCO3, 2M HCl, water and brine. The organic phase was dried and evaporated. The residue was purified by chromatography in ethyl acetate/hexane (1:9-1:4) to give the title compound as a colourless solid (51 mg, 50%). LCMS: Rt=4.10 min. [M+H] 580
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](Cl)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([CH3:39])=[CH:33]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][C:34]([CH3:39])=[CH:33]5)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Cl)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3ccc4[nH]c(C)cc4c3)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
A mixture of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)4chloro-6-methoxycinnoline (204 mg, 0.5 mmol), 5-hydroxy-2-methylindole (81 mg) and cesium carbonate (326 mg, 1 mmol) in DMF (2.5 ml) was stirred at 90° C. for 2 hours. After cooling, the mixture was filtered, wash ed with DMF and the volatiles were removed under vacuum. The crude product was dissolved in methylene chloride (4 ml) containing TEA (1.5 ml) and was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum. The residue was partitioned between methylene chloride and 1N aqueous sodium hydroxide. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with a gradient of methylene chloride/methanol saturated with ammonia (5/95 to 15/85). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the precipitate was filtered, washed with ether and dried under vacuum to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5yl)cinnoline (42 mg, 20%).
Reaction SMILES: Br[C:2]1[C:3]([N:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[O:20])[CH:18]=[CH2:19])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].C1COCC1>[Cl-].[Na+].O>[CH3:15][C:10]1[N:9]([C:5]2[N:6]=[C:7]([CH3:8])[C:2]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:3]=3[N:4]=2)[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: C=CC(=O)N(c1nc(-n2c(C)ccc2C)nc(C)c1Br)N1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2c(C)ccc2C)nc2c1ccc(=O)n2N1CCCC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a microwave vial was added N-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)-N-(pyrrolidin-1-yl)acrylamide (2.0 g, 4.95 mmol) silver carbonate (2.73 g, 9.89 mmol) and anhydrous THF (100 ml). The reaction suspension was bubbled in nitrogen for 2 mins and then added the palladium tetrakis tert-(triphenylphosphine) (286 mg, 0.25 mmol). After stirring at 70° C. oil bath for 3 h, the reaction mixture was cooled to R.T. and diluted with 20 ml of brine. After stirring at R.T. for 5 mins, the reaction mixture was filtered through a celite pad. The cake was washed with ethyl acetate. The layers were separated. The organic layer was washed with brine 20 ml, dried with potassium carbonate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluted with 40% etoac:hex to give the titled compound weighted 480 mg 30%
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[N:10]([S:13]([C:16]1[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][S:19][C:20]=1[CH3:21])(=[O:15])=[O:14])=[C:11]=[O:12]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]([CH3:9])[C:5](=[O:8])[N:6]([C:11]([NH:10][S:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][S:19][C:20]=2[CH3:21])(=[O:14])=[O:15])=[O:12])[N:7]=1
Reactant: COC(=O)c1csc(C)c1S(=O)(=O)N=C=O
Reactant: COc1n[nH]c(=O)n1C
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(C)c1S(=O)(=O)NC(=O)n1nc(OC)n(C)c1=O
Temperature: 70 °C
Reaction time: 5.8 h
Yield: 93.2 %

Procedure:
12.9 g of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (3) (100 mmol) were initially charged in 200 ml of xylene and heated to 70° C. At this temperature, 119 g of a 22% solution of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate (2) (100 mmol) in dry xylene were metered in. The mixture was stirred at 70° C. for a further 5.8 h. Subsequently, workup was effected at room temperature by filtering the precipitated product. After washing with 50 ml of xylene and subsequently drying, 36.4 g of methyl 4-({[(3-methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)carbonyl]amino}-sulfonyl)-5-methylthiophene-3-carboxylate (4) (91% of theory, content relative to standard: 97.5%) of melting point 201° C. were obtained.
Reaction SMILES: [CH3:1][C:2](P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C([CH:24]([CH2:37][CH2:38][CH3:39])[C:25]#[C:26][P:27](=[O:36])([O-:35])[O:28][C:29]([CH2:31][CH2:32][CH2:33][Cl:34])=[CH2:30])C>[Au].ClC(Cl)C>[CH2:1]([O:35][P:27]1(=[O:36])[CH:26]=[C:25]([CH2:24][CH2:37][CH2:38][CH3:39])[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][Cl:34])[O:28]1)[CH3:2]
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: C=C(CCCCl)OP(=O)([O-])C#CC(CC)CCC
Agent: [Au]
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(CCCCl)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Method 1—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, 5-chloropent-1-en-2yl ethylhex-1-ynylphosphonate (Example 17, 87.6 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-3-chlorpropyl-1,2-oxaphosphorin 2-oxide (82.3 mg, 94%) which is a title compound.
Reaction SMILES: [OH:1][C:2]1[C:12]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][C@@H:21]([CH:24]2[CH2:28][CH2:27][CH:26]([CH3:29])[O:25]2)[CH2:22][CH3:23])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]>CC#N.O>[OH:1][C:2]1[C:12]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][C@@H:21]([C@H:24]2[CH2:28][CH2:27][C@H:26]([CH3:29])[O:25]2)[CH2:22][CH3:23])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CC[C@@H](Nc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O)C1CCC(C)O1
Solvent: O
Solvent: CC#N
Product: CC[C@@H](Nc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O)[C@H]1CC[C@H](C)O1

Procedure:
This compound is isolated from a diastereomeric mixture of 2-hydroxy-N,N-dimethyl-3-{2-[(R)-1-(5-methyl-tetrahydrofuran-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Example 1) using reverse phase mass directed HPLC Column HICHROM HIRPB: 250×20 mm, 10 μm, eluent: 5-20% MeCN/H2O-0.1% diethylamine.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[F:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH2:23])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])[C:15]=1[F:33].O>C(Cl)Cl.C1COCC1>[F:33][C:15]1[C:16]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:6](=[O:7])[NH:23][C:17]=2[C:18]2[O:22][CH:21]=[CH:20][C:19]=2[C:14]=1[F:13]
Reactant: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.2 %

Procedure:
For scale up synthesis, CDI(92.4 g, 570 mmol) was added to a solution of 4,5-difluoro-N6-(2-fluoro-4-iodo-phenyl)-benzofuran-6,7-diamine (153.6 g, 380.1 mmol) in 1500 mL of DCM at 0° C. The solution was then warmed to room temperature and stirred for approximately 48 hours. Analysis showed 0.3% remaining of 4,5-difluoro-N6-(2-fluoro-4-iodo-phenyl)-benzofuran-6,7-diamine with 86.1% purity. The solution was filtered to give crude gray solid with 96.4% purity. The crude was dissolved in 1.5 L of THF and then water (1.5 L) was added. The suspension was then concentrated to 1.7 L and filtered to give 87 g of product with 98.0% purity (53.2% yield). 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (bs, 1H), 8.09 (d, 1H), 7.94 (dd, 1H), 7.76 (d, 1H), 7.47 (t, 1H), 7.19 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][N:8]=1)=[O:6].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O.O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:2][CH2:3][NH:4][C:5]([C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[S:9][N:8]=4)=[O:6])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Clc1ccc2c(N3CCCCC3)noc2c1
Reactant: O=C(NCCCl)c1nsc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NCCC1CCN(c2noc3cc(Cl)ccc23)CC1)c1nsc2ccccc12
Temperature: 180 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
A mixture of N-(2-chloroethyl)-1,2-benzisothiazole-3-carboxamide (2.9 g) and 1-(6-chloro-1,2-benzisoxazol-3-yl)piperidine (3.48 g) in dry N-methylpyrrolidinone (125 ml) was heated to 180° C., with stirring, under nitrogen. After 5 hr, the reaction mixture was allowed to cool to room temperature, diluted with water, basified with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica using ether as the eluent. The appropriate fractions were collected and evaporated. The residue was triturated with dichloromethane/ether to give 2.38 g (44.6%) of product, mp 132°-134° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18](=O)[CH3:19])[CH2:14][CH2:13]1.[C:21]1([CH2:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([CH3:19])[NH:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14][CH2:13]1
Reactant: CC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Reactant: NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CC(NCc1ccccc1)C1CCN(CC2COc3ccccc3O2)CC1
Yield: 100 %

Procedure:
A mixture of 10 parts of 1-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]ethanone, 3.8 parts of benzenemethanamine, 1 part of a solution of thiophene in methanol 4% and 160 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 13.2 parts (100%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-α-methyl-N-(phenylmethyl)-4-piperidinemethanamine as an oily residue (intermediate 88).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](CO)=[N:7][N:8]=1)[CH3:2].[CH:15]([Cl:18])(Cl)[Cl:16]>S(Cl)(Cl)=O>[ClH:16].[Cl:18][CH2:15][C:6]1[N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([S:3][CH2:1][CH3:2])=[N:8][N:7]=1
Reactant: ClC(Cl)Cl
Reactant: CCSc1nnc(CO)n1CC(C)C
Solvent: O=S(Cl)Cl
Product: CCSc1nnc(CCl)n1CC(C)C
Product: Cl

Procedure:
To a solution of 5-ethylthio-3-hydroxymethyl-4-isobutyl-4H-1,2,4-triazole (1.0 g) in chloroform (3 ml), thionyl chloride (8 ml) was slowly added at 0° C. The mixture was heated to reflux for 1 hour, and concentrated under reduced pressure. To the residue was added diethylether, and the precipitated crystals were collected by filtration. The crystals were washed with diethylether, to give 3-chloromethyl-5-ethylthio-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.64 g) as colorless crystals.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]([Cl:21])([Cl:20])[CH2:14][O:15][C:16](=[O:19])[CH:17]=[CH2:18].COC(=O)C([Cl:35])CC1C=CC(CO)=CC=1>>[Cl:12][C:13]([Cl:21])([Cl:20])[CH2:14][O:15][C:16](=[O:19])[CH:17]([Cl:35])[CH2:18][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cl)Cc1ccc(CO)cc1
Reactant: Nc1ccc(CCCO)cc1
Reactant: C=CC(=O)OCC(Cl)(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)C(Cl)Cc1ccc(CCCO)cc1

Procedure:
The title compound was prepared from 3-(4-amino phenyl)-propan-1-ol (1.02 g, 6.72 mmol) and acrylic acid 2,2,2-trichloroethylester (4.55 g, 22.17 mmol) in the same manner as described for 2-chloro-3-(4-hydroxymethyl-phenyl)-propionic acid methyl ester. The crude product was purified by flash chromatography using DCM/iPrOH 95:5 as the eluent and the product was obtained as an oil (0.74 g, 29.4%). 1H NMR (300 MHz, CDCl3): δ 7.08-7.30 (m, 4H), 4.56-4.60 (t, 1H), 3.63-3.65 (m, 3H), 3.35-3.43 (dd, 1H), 3.18-3.25 (dd, 1H), 2.63-2.68 (m, 3H), 1.84-1.86 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:25])[O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])=[CH:18][C:17]=1[F:23])[CH3:2]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CCNC(=O)Oc1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Solvent: ClCCl
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl ethylcarbamate (10 mg, 0.029 mmol) in CH2Cl2 (1 mL) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate (2 mL, 0.25 M in dichloroethane). The reaction was stirred at room temperature for 1 h, LC/MS analysis indicated consumption of starting carbamate. The mixture was concentrated in vacuo and the residue was suspended in methanol and filtered to give the title compound. The filtrate was purified by flash chromatography to provide more of the title compound as a pale yellow solid (combined yield 5.9 mg, 40%). 1H NMR (CDCl3) 10.63 (s, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.67 (dd, 1H, J=12.1, 2.2 Hz), 7.28 (m, 4H), 7.10 (m, 2H), 3.73 (s, 3H), 3.36 (m, 2H), 2.48 (s, 3H), 1.26 (m, 3H); MS(ESI+) m/z 525 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[Cl:13])[NH:6][CH:5]=1)#[N:2].C(O)(=O)/C=C/[C:19]([OH:21])=[O:20].[CH3:24][OH:25]>CNC.[Ni]>[C:19]([OH:21])(=[O:20])[C:24]([OH:14])=[O:25].[NH2:2][CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[Cl:13])[NH:6][CH:5]=1
Reactant: CO
Reactant: O=C(O)/C=C/C(=O)O
Reactant: COc1ccc2[nH]cc(CC#N)c2c1Cl
Agent: [Ni]
Agent: CNC
Product: COc1ccc2[nH]cc(CCN)c2c1Cl
Product: O=C(O)C(=O)O

Procedure:
Reductive amination of 3-cyanomethyl-4-chloro-5-methoxyindole (3.82 g, 17.3 mmol) in methanol (200 ml) and dimethylamine (40 ml) over Raney nickel for 21/2 hours at 15 p.s.i. pressure, at room temperature, followed by removal of catalyst and solvent gave a crude product containing two major components. Separation by chromatography (SiO2 ; CHCl3 /MeOH) gave two products. Part of the less polar product (650 mg of 2.13 g) was dissolved in methanol and treated with a solution of excess fumaric acid in methanol. On treatment with diethyl ether and refrigeration, the product, 3-(2-dimethylaminoethyl)-4-chloro-5-methoxyindole fumarate (494 mg) crystallised out, m.p. 223°-5° C. The whole of the more polar product was treated with a solution of oxalic acid in methanol to give 3-(2-aminoethyl)-4-chloro-5-methoxyindole oxalate. Recrystallisation from methanol gave 301 mg, dec > 230° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccc(C(F)(F)F)o3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 55 mg (0.20 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 10 mg of 60% sodium hydride, 55 mg (0.24 mmol) 2-bromomethyl-5-trifluoromethyl-furan and 0.7 mL of N,N-dimethylformamide. Yield: 70 mg of a white solid: LC-MSD, m/z for C24H18F3NO3 [M+H]+=426.4; HPLC retention time: 2.7 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:25][CH2:26][C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]([CH3:37])([CH3:36])[O:33][C:34](=[O:35])[C:29]=2[CH:28]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:25][CH2:26][C:27]3[CH:39]=[CH:38][C:30]4[O:31][C:32]([CH3:37])([CH3:36])[O:33][C:34](=[O:35])[C:29]=4[CH:28]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(CN)ccc2O1
Solvent: CC(=O)O
Product: CCCCc1ccc(C#Cc2ccc(CNCc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and 6-(aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one acetate as a yellow oil (83%). 1H NMR (CDCl3, 300 MHz) δ 7.91 (s, 1H), 7.55 (m, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.14 (m, 2H), 6.92 (d, J=8.3 Hz, 1H), 3.80 (s, 2H), 3.77 (s, 2H), 2.61 (m, 2H), 1.72 (s, 6H), 1.65-1.54 (m, 2H), 1.43-1.10 (m, 2H), 0.92 (m, 3H). M+ (ESI): 454.4. HPLC, Rt: 4.23 min (Purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=4)[C:15](=[O:28])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:32].[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNC>CN1CCCC1=O>[CH3:30][N:31]([CH3:32])[C:25]([C:23]1[N:24]=[C:20]([CH2:19][N:16]2[CH2:17][CH2:18][N:13]([S:10]([C:8]3[S:7][C:6]4[CH:29]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:14][C:15]2=[O:28])[S:21][CH:22]=1)=[O:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid (14 mg, 0.03 mmol) in N-methyl-pyrolidinone (0.3 mL) is added TBTU (0.05 mmol) and diisopropylethylamine (0.06 mmol) and dimethylamine hydrochloride (0.06). The reaction is stirred 3 h and an additional aliquot of TBTU, DIEA and amine are added. The reaction is stirred 1 h and the reaction is concentrated and purified by column chromatography (silica, 2% MeOH/EtOAc) to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazole-4-carboxylic acid dimethylamide. 1H NMR (300 MHz, CDCl3) δ 7.87-7.77 (m, 4H), 7.47 (dd, 1H), 4.83 (s, 2H), 3.92 (s, 2H), 3.63-3.60 (m, 2H), 3.47-3.43 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H); MS (Ion Spray) 499 (M+H)+.