Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.C1C=CC=CC=1.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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: c1ccccc1
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 50.2 %

Procedure:
In 50 ml of diethylamine were dissolved 5.0 g (22 mmol) of 4-bromo-α, α,α-trifluorotoluene and 1.25 g (22 mmol) of propargyl alcohol, and 80 mg (0.11 mmol) of bis(triphenylphosphine)palladium (II) chloride and 40 mg (0.22 mmol) of copper (I) iodide were added to the solution, followed by stirring of the resulting mixture at 50° C. for 35 minutes. To the mixture were added 40 mg (0.06 mmol) of bis(triphenylphosphine)palladium (II) chloride, and the resulting mixture was stirred for a further 35 minutes. After the mixture was cooled to room temperature, it was diluted with benzene and filtered, and then the filtrate was washed with water. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 50 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to obtain 2.21 g (yield: 50%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.[NH2:10][C:11]1[S:12][C:13]2[CH2:22][CH2:21][CH2:20][CH2:19][C:14]=2[C:15]=1[C:16](N)=[O:17]>S(Cl)(Cl)=O.O1CCOCC1.O>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([NH:10][CH:11]1[S:12][C:13]2[CH2:22][CH2:21][CH2:20][CH2:19][C:14]=2[C:15]1=[C:16]=[O:17])=[O:6]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: COC(=O)CCC(=O)O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)CCC(=O)NC1SC2=C(CCCC2)C1=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Monomethyl hydrogen succinate (4.7 g, 0.035 mol) was refluxed in thionyl chloride (20 ml) for 2 hrs. After consumption of starting material, excess of thionyl chloride was distilled off. The reaction mixture dissolved in dioxane (10 ml) and was added drop wise to 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide 1 (7 g, 0.035 moles) in dioxane (10 ml) at 0° C. and stirred at room temperature (R.T) for 2 hrs. The reaction mixture was diluted with water to give crude product which was filtered and washed with water. The crude was purified by chromatography on silica gel using 1:1 Ethyl acetate:Hexane to give 5 g (46%) of N-(3-carbonyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-succinamic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=1.72 (m, 4H), 2.6 (m, 4H), 2.68 (m, 4H), 3.59 (s, 3H), 6.99 (s, 1H), 7.55 (s, 1H), 11.48 (s, 1H). LC-MS: [M−H]=308.9.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([OH:10])=O)[CH3:3].[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:24]=1>>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C:8]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:24]=2)=[O:10])[CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:1]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Product: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1

Procedure:
The preparations of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate were described earlier.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:8]([C:7]3[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[O:10])[CH2:24][CH2:25]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3nsc4ccccc34)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example 2.6) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: OC1C=CC=CC=1/C=[N:5]\[C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]1[S:30][C:31]([CH3:34])=[N:32][N:33]=1)=[C:11]2[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16].O.CS([O:44][C:45](=O)[CH2:46][N:47]1[CH:51]=[N:50][N:49]=[N:48]1)(=O)=O.ClCCl>C(OC)(C)(C)C>[N:47]1([CH2:46][C:45]([NH:5][C@@H:6]2[C:13](=[O:14])[N:12]3[C@@H:7]2[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]2[S:30][C:31]([CH3:34])=[N:32][N:33]=2)=[C:11]3[C:15]([OH:17])=[O:16])=[O:44])[CH:51]=[N:50][N:49]=[N:48]1
Reactant: COc1ccc(COC(=O)C2=C(CSc3nnc(C)s3)CS[C@@H]3[C@H](/N=C\c4ccccc4O)C(=O)N23)cc1
Reactant: CS(=O)(=O)OC(=O)Cn1cnnn1
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (6R,7R)-4-methoxybenzyl 7-((Z)-(2-hydroxybenzylidene)amino)-3-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), 2-(1H-tetrazol-1-yl)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 88.3 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)pyrrolidin-3-ylcarbamate (417 mg, 1.5 mmol) to afford the desired product (488 mg, 88%) as a yellow solid: ESI MS m/z 552 [C27H30BrN5O3+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([Br:12])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:13]([OH:15])=[O:14].C(O)(=O)C.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>O>[Br:1][C:2]1[C:11]([Br:12])=[C:10]([N+:20]([O-:22])=[O:21])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(Br)c(Br)cc2c1OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Temperature: 37 °C
Yield: 83 %

Procedure:
A 20-mL round bottom flask was charged with 6,7-dibromo-2,3-dihydrobenzo[b][1,4]dio-xine-5-carboxylic acid (3.0 g, 0.61 mmol) and acetic acid (2 mL). The mixture was heated to 37° C., following by the addition of a solution of nitric acid (d=1.49, 1.0 mL), acetic acid (1.0 mL) and concentrated sulfuric acid (1.0 mL). After heating at 50° C. for 1 h, the mixture was poured in cold water while stirring. It was then filtered and the solid was washed with water to afforded the title compound (1.91 g, 83%). LCMS: ESI (3 minute run), m/z=382 [M+1]+; Retention time: 1.05 minute.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3cccnc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cncc(-c2cnc(NC3CCNCC3)nc2)c1

Procedure:
A solution of 4-(5-pyridin-3-yl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.68 g, 1.91 mmol) in 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 256.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[O-])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH3:32])[N:24]=[CH:23][N:22]=[C:21]2[S:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([S:33][C:21]3[C:20]4[C:25](=[CH:26][C:27]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:18]([O:17][CH3:16])[CH:19]=4)[N:24]=[CH:23][N:22]=3)[CH:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C([O-])Nc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(F)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react 3-fluoro-4-(trifluoromethyl)phenylcarbamate as described in Example 150 (138 mg, 0.46 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (110 mg, 0.31 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with dichloromethane to give 122 mg. 1H (DMSO-d6) 9.43 (s, 1H), 9.15 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.70 (m, 2H), 7.60 (m, 1H), 7.50 (m, 1H), 7.40 (m, 4H), 4.34 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.38 (m, 3H). LCMS (ESI) m/z 563 (M+H)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:10][B-:11]([F:14])([F:13])[F:12].[Na+].[F:16]F>C(#N)C>[F:10][B-:11]([F:14])([F:13])[F:12].[F:10][B-:11]([F:14])([F:13])[F:12].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:16])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: [O-][N+]12CCN(CC1)CC2
Reactant: FF
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 70 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (1.26 g, 9.8 mmole) and sodium tetrafluoroborate (1 g, 9.1 mmole) in acetonitrile (250 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 30 mmole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 1.03 grams of 1-hydroxyl-4-fluoro- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (70% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of step i) (170 mg) in methanol (5 mL) was added 4M HCl in 1,4-dioxane (5 mL). The solution was stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the residue was purified by HPLC to yield the title compound as a solid (25 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[CH:17][CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K77) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (100 mg).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH2:2][O:10]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccncn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccncn2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
Trimethylsulfonium iodide (3.34 g, 16.3 mmol) was dissolved in DMF (20 mL) and stirred at RT for 5 min. Sodium hydride (600 mg, 25 mmol) was added portionwise at the same temperature and stirred for 15 min. 4-Acetyl pyrimidine (1 g, 8.1 mmol) in 0.5 mL DMSO was added dropwise and the reaction mixture stirred for 1 h. After completion of reaction, the mixture was poured into ice-cold water and extracted with Ether (3×). The combined organic layer was washed with water several times followed by brine, and dried over sodium sulfate, then evaporated to provide 600 mg of 4-(2-Methyl-oxiranyl)-pyrimidine. 1H NMR (CDCl3, freebase) δ (ppm): 9.15 (s, 1H), 8.7 (d, 1H), 7.35 (d, 1H), 2.95 (d, 1H), 2.88 (d, 1H), 1.8 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][C:13]1([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][C:13]([CH3:12])([OH:19])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: CC1(O)CCNCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: CC1(O)CCN(c2nnc3ccc(F)cn23)CC1
Temperature: 170 °C
Yield: 32.7 %

Procedure:
A mixture of Intermediate 24b (400 mg, 2.32 mmol) and Intermediate 79b (1.33 g, 11.6 mmol) in NMP (5 mL) was heated in the microwave at 170° C. for 3 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-8% [2M NH3 in MeOH] in DCM, gave the title compound (190 mg, 32%). LCMS (Method 1): Rt 2.01 min, m/z 251 [MH+].
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:33]N)=[O:32]>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19][NH:33][C:31]([C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[O:32]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Reactant: NNC(=O)c1cccs1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNC(=O)c1cccs1)C(=O)N2
Yield: 35 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2- one and 2-thiophene carboxylic acid hydrazide and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: C([O-])(O)=O.[Na+].[I:6]N1C(=O)CCC1=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22](C(O)=O)=[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[N:24]3[N:25]=2)=[CH:17][CH:16]=1.O>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([I:6])=[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[N:24]3[N:25]=2)=[CH:17][CH:16]=1
Reactant: CC1CCc2c(C(=O)O)c(-c3ccc(F)cc3)nn21
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCc2c(I)c(-c3ccc(F)cc3)nn21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.1 g (36.9 mmol) of NaHCO3 and 2.8 g (12.3 mmol) of N-iodosuccinimide are added to a solution of 3.2 g (12.3 mmol) of 2-(4-fluorophenyl)-6-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid in 25 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 16 h, water is added and the precipitated solid is filtered off and dried. This gives 3.30 g of the desired product in a purity of 77% which are reacted further without further purification: (log P(HCOOH): 3.82); 1H-NMR (ppm): δ (DMSO-d6)=1.42 (d, 3H), 2.11-2.18 (m, 1H), 2.72-2.82 (m, 3H), 4.49 (m, 1H), 7.28 (dd, 2H), 7.79 (dd, 2H); LC-MS: m/z=343 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23](CC#N)=[CH:22][C:21]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8].C(OCC)(=O)C.[C:43]([OH:46])(=[O:45])[CH3:44]>>[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][C:23]([CH2:44][C:43]([OH:46])=[O:45])=[CH:22][C:21]=3[C:33]([F:36])([F:34])[F:35])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC(=O)O)cc3C(F)(F)F)cc12
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of 5 ml of concentrated sulphuric acid and 5 ml of water is added dropwise to a solution of 0.35 g (0.82 mmol) of nitrile derivative from Example VIII in 5 ml of acetic acid (100% strength). The reaction solution is stirred at 105° C. for 4 hours, then cooled to room temperature and treated with ice-cold water and ethyl acetate. The organic phase is separated off, the aqueous solution is extracted again with ethyl acetate, and the combined organic phases are dried over sodium sulphate, filtered and concentrated to give an oil. The crude product (120.3 mg) is chromatographed on silica gel 60 by means of methylene chloride/methanol (95:5 and95:11).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1>C(#N)C>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2)[S:32]([C:29]1[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=1)(=[O:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCc2cc(NCc3ccccc3)ccc21
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3=O)n1
Temperature: 150 °C
Yield: 14 %

Procedure:
To a stirred solution of 6-benzylamino-3,4-dihydro-2H-isoquinolin-1-one (45 mg, 0.18 mmol) and pyridine (31 μl, 0.39 mmol) in anhydrous acetonitrile (1 ml) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (70 mg, 0.39 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the crude residue purified by preparative tlc (5% methanol in dichloromethane) to afford the title compound as a yellow solid (10 mg, 14%). HPLC retention time 3.83 min. Mass spectrum (ES+) m/z 397 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.CCN=C=NCCCN(C)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)/[CH:43]=[CH:44]/C(O)=O>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6](=[O:7])/[CH:44]=[CH:43]/[C:42]2[CH:48]=[CH:49][CH:50]=[C:40]([O:39][CH3:38])[CH:41]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: COc1cccc(/C=C/C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cccc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2ccccc32)c1
Yield: 73.7 %

Procedure:
Deprotection of 13 (250 mg, 0.69 mmol) as in Example C above, and reaction of the product with EDCI.HCl (331 mg, 1.73 mmol), (E)-3-methoxycinnamic acid (129 mg, 0.72 mmol) and DMA (3 mL) at 20° C. for 3 h, followed by addition of dilute KHCO3, gave a solid. This was recrystallised from CH2Cl2 /i-Pr2O followed by EtOAc to give 14l (215 mg, 74%), mp 200° C. 1H NMR [(CD3)2SO] δ 9.22 (s, 1 H, H-4), 8.33 (dd, J=7.9, 1.8 Hz, 1 H, H-6), 8.19 (dd, J=7.5, 1.7 Hz, 1 H, H-9), 7.78-7.68 (m, 2 H, H-7,8), 7.72 (d, J=15.4 Hz, 1 H, PhCH=CH), 7.45-7.34 (m, 2 H, H-5',6'), 7.39 (s, 1 H, H-2'), 7.26 (d, J=15.4 Hz, 1 H, PhCH=CH), 7.02 (dt, J=7.2, 2.2 Hz), 1 H, H-4'), 4.71-4.56 (m, 3 H, H-1,2), 4.11-4.05 (m, 2 H, CH2Cl), 3.84 (s, 3 H, CH3). Anal. Calculated for C23H19ClN2O4 : C, 65.3; H, 4.5; N, 6.6; Cl, 8.4. Found: C, 65.0; H, 4.6; N, 6.6; Cl, 8.5%.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:38])[CH3:37])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH2:26][CH2:27]1)=[O:30]
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CNC
Product: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)N(C)C)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 57 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 57% of theory; LC (method 3): tR=3.07 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Temperature: 20 °C
Yield: 83.6 %

Procedure:
A solution of KOH (6.7 g, 118.45 mmol) in methanol (60 mL) was added to 5-bromo-1H-indole (10 g, 50.51 mmol) in a 250 mL 3-necked round bottom flask. 1-methylpiperidin-4-one (7.7 g, 67.46 mmol) was then added dropwise with stirring, while cooling to a temperature of 20° C. The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at 73° C. The reaction mixture was then cooled to 15° C. and filtered. The filter cake was washed with water (3×50 mL). The product was purified by recrystallization from ethanol to afford 12.3 g (83%) of 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a white solid.