Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCCSCc1c(F)cccc1Cl
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCSCc1c(F)cccc1Cl)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(2-chloro-6-fluorobenzylsulfanyl)ethylamine. The product was purified by mass directed purification to give the title compound as a yellow solid. δH (CD3OD): 2.82 (2H, t), 3.64 (2H, t), 3.95 (2H, s), 7.04-7.09 (2H, m), 7.20-7.25 (2H, m), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [C:1]12([C:11]3[CH:35]=[CH:34][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]([N+:31]([O-])=O)=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd].CO>[C:1]12([C:11]3[CH:35]=[CH:34][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]([NH2:31])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1N
Yield: 99.7 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-{5-[4-(1-adamantyl)phenoxy]-2-nitrophenyl}-N-methylcarbamate (4.28 g), palladium on carbon (10%, 0.42 g) and methanol (60 ml) and the reaction mixture was purified to give the title compound (4.00 g).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]=[O:13].[OH-].[K+].[CH2:16]([OH:18])C>>[C:1]1([C:7]2[NH:11][C:10]([CH2:16][OH:18])=[C:9]([CH2:12][OH:13])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: C=O
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Product: OCc1nc(-c2ccccc2)[nH]c1CO
Yield: 92 %

Procedure:
Twenty nine grams (0.2 mole) of 2-phenylimidazole, 19 g (0.6 mole) of paraformaldehyde, 5.6 g (0.1 mole) of potassium hydroxide and 50 ml of ethanol were heated under reflux for 1.5 hours with stirring, cooled, and post-treated in the same way as in Example 1, to afford somewhat pale brown 2-phenyl-4,5-dihydroxymethyl imidazole as a final product in an amount of 37.8 g (yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]1[N:31]([CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:34][CH2:33][CH2:32][N:31]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(4-morpholino)ethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.79 (1H, s), 10.76 (1H, br s), 10.12 (1H, br), 8.18 (1H, m), 7.35-7.24 (3H, m), 7.12 (2H, br m), 3.98 (2H, br s), 3.56 (4H, m), 3.40 (2H, m), 2.39 (6H, m); ES+ MS: 427 (M+H+, 100).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1.[CH3:15][C:16]([S:19]([N:21]=[C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:20])([CH3:18])[CH3:17].C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:18][C:16]([S:19]([NH:21][C:22]1([C:13]2[S:14][C:10]([CH3:9])=[CH:11][N:12]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:20])([CH3:15])[CH3:17]
Reactant: Cc1cncs1
Reactant: CC(C)(C)S(=O)N=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cnc(C2(NS(=O)C(C)(C)C)CCOCC2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A 2.0M solution of lithium diisopropylamide in THF (492 μl, 984 μmol) was added dropwise to a solution of 5-methylthiazole (97.5 mg, 984 μmol) in dry THF (0.3 ml) cooled to −78° C. and once the addition was complete the reaction was stirred for 30 minutes at −78° C. followed by addition of dry toluene (0.6 ml). To a solution of 2-methyl-N-(2H-pyran-4(3H,5H,6H)-ylidene)propane-2-sulfinamide (CAN 861857-62-7, 100 mg, 492 μmol) in dry toluene (1 mL) was added a 2.0M solution of trimethylaluminum in heptane (271 μl, 541 μmol). The former solution was then added to the reaction mixture cooled at −78° C. The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and was then diluted with ethyl acetate. The bi-phasic mixture was poured into a separatory funnel and extracted. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane-methanol gradient to yield the title compound (102 mg, 69%). MS (ESI, m/z): 303.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
300 mg (1.04 mmol) of the compound of Example 6A, 301 mg (1.14 mmol) of the compound of Example 24A and 473 mg (1.24 mmol) of HATU were initially charged in 3.6 ml of DMF, 0.36 ml (2.07 mmol) of N,N-diisopropylethylamine was added and the mixture was stirred at RT for two days. The reaction was then directly separated into its components by preparative HPLC (Method 18). This gave 180 mg (31% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9](I)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[O:1][C:2]3[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=3[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: O=Cc1cccc(I)c1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(-c2cc3cccc(C=O)c3o2)c1
Yield: 143 %

Procedure:
A mixture of 11 g of 2-hydroxy-3-iodo benzaldehyde, 8.6 g of (3-methoxy-phenyl) acetylene and 150 ml of pyridine was refluxed for 45 minutes and then allowed to return to ambient temperature. Ethyl acetate was added, and washing was carried out with an acid solution, followed by drying and concentrating to obtain 16 g of product which was chromatographed on silica (eluant: hexane-isopropyl ether (7-3)) to obtain 9 g of the desired product melting at 55° C. to 60° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]2=[O:21])=[CH:7][CH:6]=1.[Cl:24][C:25]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([S:31]([N:18]2[CH2:17][CH2:16][C:13]3([C:12](=[O:21])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:6][CH:7]=4)[CH2:15][CH2:14]3)[CH2:20][CH2:19]2)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (prepared in analogy to example 180 step B-D using 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester and 4-(2,2,2-trifluoro-ethoxy)aniline) and 2-chloro-pyridine-3-sulfonyl chloride. White solid. MS (ESI): 504.1 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:11][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:12])=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(C=CC(=O)c2ccc3c(c2)CCC3)cc1

Procedure:
A solution of 4.8 g of 1-(2,3-dihydro-1H-inden-5-yl)ethanone 5; 30 mmoles), 4.5 g of p-dimethylaminobenzaldehyde (30 mmoles), and 1.32 g of sodium hydroxide in 40 ml of methanol was stirred under nitrogen at room temperature for 48 hr. The reaction mixture was cooled in an ice bath and the precipitated solid 3-[4-(dimethylamino)phenyl]-1-(2,3-dihydro-1H-inden-5-yl)-2-propen-1-one was collected by filtration and washed with cold methanol. Yield: 4.2 g (48%); m.p. 106° to 108°. λmax (EtOH): 416 nm (ε=34,700); 272 nm (15,400). Calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.19, 82.12; H, 7.21, 7.24; N, 4.70, 4.67.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[C:18](Cl)(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(O)CCCC=CC1C2CCC(C2)C1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCCC=CC1C2CCC(C2)C1CO
Reaction time: 16 h
Yield: 95 %

Procedure:
65.7 g (0.28 mole) of 6-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-hex-5-enoic acid are heated under reflux in 220 ml of methanol and 600 ml of carbon tetrachloride with the addition of 6.0 g (0.03 mole) of p-toluenesulphonic acid, for 16 hours. The mixture is then washed 3 times with 500 ml of saturated aqueous sodium bicarbonate solution and twice with 500 ml of saturated aqueous sodium chloride solution. The mixture is dried over sodium sulphate and the solvents are then evaporated off in vacuo. 66.4 g (yield: 95%) of methyl 6-(3-hydroxymethyl-bicyclo-[2.2.1]hept-2-yl)-hex-5-enoate are obtained.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:14]3[C:9](=[C:10]([N:39]4[CH2:44][CH2:43][CH:42]([C:45]([O:47]CC)=[O:46])[CH2:41][CH2:40]4)[CH:11]=[C:12]([C:15]([N:17]4[CH2:22][CH2:21][C:20]5([CH2:31][C:30](=[O:32])[C:29]6[C:24](=[CH:25][CH:26]=[C:27]([C:33]7[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=7)[CH:28]=6)[O:23]5)[CH2:19][CH2:18]4)=[O:16])[CH:13]=3)[CH:8]=[CH:7]2)[CH2:5][CH2:4]1.CO.Cl>C1COCC1>[CH:3]1([N:6]2[C:14]3[C:9](=[C:10]([N:39]4[CH2:44][CH2:43][CH:42]([C:45]([OH:47])=[O:46])[CH2:41][CH2:40]4)[CH:11]=[C:12]([C:15]([N:17]4[CH2:18][CH2:19][C:20]5([CH2:31][C:30](=[O:32])[C:29]6[C:24](=[CH:25][CH:26]=[C:27]([C:33]7[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=7)[CH:28]=6)[O:23]5)[CH2:21][CH2:22]4)=[O:16])[CH:13]=3)[CH:8]=[CH:7]2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCN(c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc3c2ccn3C2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(N5CCC(C(=O)O)CC5)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
Aqueous 1N NaOH (0.409 ml, 0.409 mmol) was added to a stirred solution of ethyl 1-(1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl)piperidine-4-carboxylate in THF (1 ml)-MeOH (1 ml) and the mixture was stirred at room temperature overnight. Aqueous 1N HCl (0.409 ml) was added to the mixture and the solvent was evaporated under reduced pressure. The residue was suspended in CHCl3-MeOH (8:2) and the mixture stirred for 1 h. at room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The crude material was purified by preparative HPLC (ODS, 0.1% HCOOH in H2O/MeCN, gradient) to give intended compound (44.4 mg, 0.073 mmol, 35.7% yield) as a pale orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:31]5[CH2:32][CH2:33][N:28]([CH2:34][CH2:35][OH:36])[CH2:29][CH2:30]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCN(CCO)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-(piperazin-1-yl)ethanol via General Procedure B. The product was purified via reverse phase HPLC to give 20.7 mg of 244. MS (Q1) 493.8 (M)+
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:5]([NH:7][C:8]1([C:17]#[N:18])[CH2:13][CH2:12][N:11]([CH2:14]CC)[CH2:10][CH2:9]1)=[O:6].[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].C(N(CC)[C:36]([S:38][C:39]#[N:40])=[O:37])C>C(#N)C>[C:17]([C:8]1([NH:7][C:5](=[O:6])[CH:4]([NH:3][C:39]([NH:40][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[S:38]=[C:36]=[O:37])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)#[N:18]
Reactant: CCN(CC)CC
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CCN(CC)C(=O)SC#N
Agent: Cl
Solvent: CC#N
Product: CCN(CC)NC(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)=S=C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of 2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt (560 mg, 1.53 mmol) and triethylamine (500 μL, 3.59 mmol) in acetonitrile (4 mL) was treated with a solution of N,N-diethyl carbamoyl thiocyanate in acetonitrile (3.0 mL, 2.7 mmol). The reaction mixture was stirred overnight at room temperature and concentrated on a rotary evaporator. The resulting residue was chromatographed (ethyl acetate:hexanes 1:1 then ethyl acetate and finally methanol:methylene chloride 1:9 as the eluant) to provide the desired product as a light yellow solid (340 mg, 49%). MS, m/z 451.3=M+1.
Reaction SMILES: C(N1[C:12]2[C:7](=[C:8]([F:14])[C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6]C1=O)(=O)C.[H-].[Na+].I[CH3:19].[CH3:20][N:21]([CH:23]=[O:24])C>>[F:13][C:9]1[C:8]([F:14])=[CH:7][CH:6]=[C:20]2[C:10]=1[C:11]([CH3:12])([CH3:19])[C:23](=[O:24])[NH:21]2
Reactant: CC(=O)N1C(=O)Cc2c1ccc(F)c2F
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC1(C)C(=O)Nc2ccc(F)c(F)c21
Reaction time: 1 h

Procedure:
0.50 g (2.4 mmol) 1-acetyl-4,5-difluoro-1,3-dihydro-indol-2-one were placed in 10 mL DMF under argon. 0.22 g (5.1 mmol) sodium hydride (55%) were added at 0° C. and the reaction mixture was stirred for 1 h. Then 0.32 mL (5.1 mmol) iodomethane were added dropwise. The reaction mixture was stirred overnight at RT, poured onto water and extracted with EtOAc. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was purified by HPLC. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[C:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:16](=[O:18])[CH3:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(C)=O)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-acetyl-benzenesulfonyl chloride (288 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12h as a solid (346 mg, 96.2%). HPLC: 99.72% (Rt=6.56 min).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[Na+].[H][H].[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27](Cl)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:3][C:2]2=[O:10])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)n2c(=O)[nH]c3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 1H-benzo[d]imidazol-2(3H)-one (268 mg, 2 mmol) in DMF (10 mL) at 0° C. was added 60% oily sodium hydride (88 mg, 2.2 mmol). When hydrogen evolution had ceased, a solution of (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride (240 mg, 0.75 mmol) in DMF (3 mL) was added and the reaction mixture allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by addition of 1N hydrochloric acid, and extracted with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by flash column (hexane-EtOAc, 25:10) to give (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one (240 mg, 37%). LC-MS (ES-API); rt 9.02 min; m/z calculated for C18H16N2O4 [M+H]+ 325.1, found 325.0 and 347.0 ([M+Na]+).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C(=O)=O.CC(C)=O.C[O:17][C:18]([C:20]1([O:23][CH3:24])[CH2:22][CH2:21]1)=O.C(#N)C>C1COCC1>[CH3:24][O:23][C:20]1([C:18](=[O:17])[CH2:2][C:3]#[N:5])[CH2:22][CH2:21]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(OC)CC1
Agent: O=C=O
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC1(C(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Add a solution of 2 M LDA in THF (29.1 mL, 58.3 mmol) to a dry ice-acetone cooled solution of 1-methoxy-cyclopropanecarboxylic acid methyl ester (WO2005/014577) (3.45 g, 26.5 mmol) and acetonitrile (2.17 g mL, 53.0 mmol) in THF (30 mL). Stir the reaction mixture at −78° C. for 1 hour and then at 22° C. for 0.5 hour. Evaporate the solvent to give a brown solid. Filter and wash with hexanes. Add 2N hydrochloric acid and extract three times with diethyl ether (50 mL each). Dry the combined organic phases over sodium sulfate. Removal of solvent provides a red oil (3.55 g, 96% yield, ES+(m/z) 140.1 [M+H]).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]([O:12][S:32]([CH3:31])(=[O:34])=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Br)cc2)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
The product from Example 191B (3.14 g, 7.84 mmole) was dissolved in 70 mL CH2Cl2 and cooled in an ice-acetone bath to −10° C. Triethylamine (3.82 mL, 27.4 mmole) was added dropwise to the cold solution, followed by dropwise addition of methanesulfonyl chloride (1.53 mL, 19.59 mmole) in 20 mL CH2Cl2 over 10 minutes. The resulting clear solution was stirred in the cold for 90 min. The reaction was deemed complete by LC-MS analysis and the solvent was removed in vacuo leaving a light yellow solid as the title compound, (4.36 g, 100%), that was used directly in the next reaction.
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:16])(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]=[C:50]=[O:51].[C:52]([O:56][CH2:57][CH2:58][CH:59](O)[CH3:60])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH:58]([O:51][C:50](=[O:16])[NH:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[S:42][CH3:41])[CH2:59][CH3:60])(=[O:55])[CH:53]=[CH2:54]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCC(C)O
Reactant: CSc1ccccc1N=C=O
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(CC)OC(=O)Nc1ccccc1SC
Temperature: 60 °C

Procedure:
0.008 g of 2,6-di-tert-butyl-4-methylphenol, 0.004 g of Desmorapid Z, 4.3 g of 2-(methylthio)phenyl isocyanate in 8.5 g ethyl acetate were initially introduced into a 50 ml round-bottomed flask and heated to 60° C. Thereafter, 4 g of 3-hydroxybutyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a light yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:16]([Cl:17])=[C:15]2[C:11]([CH2:12][C:13]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)([CH3:19])[C:14]2=[O:18])=[CH:10][C:9]=1[OH:26].[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30]>CN(C)C=O>[F:27][C:28]([F:34])([F:33])[S:29]([O:26][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:17])[C:8]=1[Cl:7])[C:14](=[O:18])[C:13]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1)([CH3:19])[CH2:12]2)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC1(CC2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CC2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous potassium carbonate (17.7 g., 0.128 mole) is added to a solution of 6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (13.35 g., 0.0426 mole) in dry dimethylformamide (60 ml.) The suspension is stirred for 1 hour at room temperature, cooled to 15° C. and then trifluoromethanesulfonyl chloride is added at 15°-18° C. After stirring for 1 hour at room temperature, the reaction mixture is poured into ice water (700 ml.). The oil that separates is extracted with ether (125 ml.). The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to obtain the amber, oily product (18.8 g.), which is used in the next step without further purification.