Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]4[N:18]([N:22]=[C:23](CC#N)[CH:24]=4)[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:28][C:29]([OH:31])=[O:30]>>[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]4[N:18]([N:22]=[C:23]([CH2:28][C:29]([OH:31])=[O:30])[CH:24]=4)[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:6]3[CH2:5][CH:4]([CH2:10][CH:8]([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: N#CCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Temperature: 60 °C

Procedure:
A solution of conc. HCl (2.3 mL) and AcOH (4.6 mL) is added to 2-cyanomethylpyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)amide. The solution is warmed to 60° C. for 20 h. The volatiles are removed under reduced pressure, and the residue is dissolved in 1 M aq. NaOH (10 mL). The solution is washed with Et2O (20 mL). The aqueous layer is acidified to ˜pH 3 with 1 M aq. HCl. The mixture is filtered and the filtrate dried to afford the title compound as a light tan solid. 1H NMR (400 MHz, ((CD3)2SO) δ: 8.71 (d, 1H), 8.40 (bt, 1H), 7.60 (d, 1H), 6.90 (t, 1H), 6.79 (s, 1H), 3.75 (s, 2H), 2.99 (d, 2H), 1.88-1.96 (m, 3H), 1.46-1.70 (m, 12H). LC-MS m/z+H+): 368.3; RT=1.27 min.
Reaction SMILES: CC[CH2:3][O:4][CH2:5][CH2:6][N:7]([C:18]([CH2:20][Cl:21])=[O:19])[C:8]1[C:9]([CH2:16][CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14]C.[CH3:22]C1C(N(C(CCl)=O)CCOC)=C(C)C=CC=1.CCC1C=CC=C(CC)C=1N(C(CCl)=O)COC.CC(N(C(CCl)=O)C1C=CC=CC=1)C.CCC1C=CC=C(C)C=1N(C(CCl)=O)COCC>>[CH3:17][CH2:16][C:9]1[C:8]([N:7]([C:18]([CH2:20][Cl:21])=[O:19])[CH:6]([CH2:5][O:4][CH3:3])[CH3:22])=[C:13]([CH3:14])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCOCCN(C(=O)CCl)c1c(CC)cccc1CC
Reactant: COCCN(C(=O)CCl)c1c(C)cccc1C
Agent: CC(C)N(C(=O)CCl)c1ccccc1
Agent: CCOCN(C(=O)CCl)c1c(C)cccc1CC
Agent: CCc1cccc(CC)c1N(COC)C(=O)CCl
Product: CCc1cccc(C)c1N(C(=O)CCl)C(C)COC

Procedure:
Pretilachlor, Dimethachlor, Alachlor, Propachlor, Trimexachlor, acetochlor.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19](O)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Si]([N:60]=[N+:61]=[N-:62])(C)(C)C>C(Cl)Cl>[N:60]([C@H:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20][OH:21])=[N+:61]=[N-:62]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](O)CO
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](CO)N=[N+]=[N-]
Reaction time: 3 h

Procedure:
To a solution of 3.17 g (10.0 mmol) of 3-O-hexadecyl-sn-glycerol (2) and 3.42 g (13.0 mmol) of Ph3P in 180 mL of CH2Cl2 was added 3.2 mL (15 mmol) of diisopropyl azodicarboxylate (DIAD) at 0° C. After the mixture was stirred for 3 h under nitrogen, Me3SiN3 was added. The mixture was stirred at the same temperature for 3 h, and then at room temperature until glycerol 2 had reacted completely. The reaction mixture was concentrated to give a yellow residue, which was dissolved in a minimum volume of CH2Cl2 and passed through a pad of silica gel in a sintered glass funnel. The pad was rinsed with hexane/EtOAc (50:1) until the excess yellow DIAD began to elute. After concentration of the eluted silyloxy azide, the residue was dissolved in 30 mL of THF and treated with 25 mL of a 1 M (n-Bu)4NF solution in THF. The mixture was stirred at room temperature until all of the silyloxy azides were consumed completely, and then was diluted with 250 mL of Et2O and washed with water and brine. The organic layer was separated, dried over Na2SO4, and concentrated The crude product was purified by column chromatography on silica gel (elution first 150 mL of 50:1 hexane/EtOAc and then with 6:1 hexane/EtOAc) to give 2.60 (76%) of azido alcohol 3 as a white solid: mp 37-39° C., (Ponpipom and Bugianesi, 1984). 38-29° C.; [α]25D +14.50 (c 1.0, CHCl3), (Ponpipom and Bugianesi 1984. [α]27D +14.1° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=6.4 Hz), 1.26 (s, 26H), 1.52-1.62 (m, 2H), 2.19 (br s, 1H), 3.47 (t, 2H, J=6.8 Hz), 3.55-3.63 (m, 4H), 3.65-3.80 (m, 1H); 13C NMR (CDCl3) δ 14.1, 22.7, 26.0, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 62.3, 63.0, 70.9, 71.9.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]3[C:21]([CH2:23][O:24][CH2:25][CH3:26])([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[CH:27]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:25]([O:24][CH2:23][C:21]1([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]2[CH:27]=[C:12](/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]1=2)[CH3:26]
Reactant: CCOCC1(C)CCCSc2cc(/C=C/c3ccc(C(=O)OC)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCC1(C)CCCSc2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Reaction time: 18 h
Yield: 89 %

Procedure:
406 mg (0.99 mmol) of (E)-4-[2-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid methyl ester was dissolved in 4 ml of THF/ethanol=1/1 and treated with 1.32 ml of 3N NaOH(4 eq). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/diluted HCl, extracted twice with ethylacetate, the organic phase was washed with a small amount of water, dried over magnesium sulfate, filtrated and the solvent evaporated. Crystallization of the residue from hexane/ethylacetate (8/2) yielded 337 mg of the title compound as white crystals of m.p. 186-187° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][C@@H:9]([NH:15]C=O)[C:10]([O:12]CC)=[O:11])(=O)C.C(Cl)Cl.C[Si](C)(C)Br>C(O)C>[NH2:15][C@H:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH2:5][OH:4])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)[C@@H](C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: N[C@H](C=C(CCO)CP(=O)(O)O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
12.7 g (30.2 mmol) of ethyl 6-acetoxy-2(R)-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 100 ml of abs. CH2Cl2 and 15.6 ml (120.8 mmol) of trimethylbromosilane are added to this solution at room temperature. The reaction mixture is allowed to stand for 24 hours at room temperature. After addition of 100 ml of abs. ethanol the reaction mixture is again allowed to stand for 24 hours at room temperature and then concentrated by evaporation. The residue is dissolved in ethanol and then a mixture of 100 ml of propylene oxide and 100 ml of ethanol is added dropwise. The suspension so obtained is stirred for 1 hour at 0° C. and then filtered with suction. The filter product is stirred overnight in ether and again filtered with suction. The filter product is dried, giving white crystals of 2(R)-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid. Melting point: 170° C. (decomp.). ee=92%; αD =-45.6°± 1° (c=1.0 H2O).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:22])=[C:15](F)[C:16]=3[N+:18]([O-:20])=[O:19])[C:11](=[O:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]2)[CH:7]=1.[CH3:29][NH2:30]>N1C=CC=CC=1>[CH3:2][NH2:1].[NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:22])=[C:15]([NH:30][CH3:29])[C:16]=3[N+:18]([O-:20])=[O:19])[C:11](=[O:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c([N+](=O)[O-])c32)c(F)cc1F
Agent: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (172 mg) of methylamine were added to pyridine (1 ml), and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and ethanol was added to the residue to collect solids by filtration. The solids were washed successively with ethanol and diethyl ether to obtain the title compound (122 mg) as an orange powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH:25]=[CH2:26])[C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH3:22])=[C:7]([CH3:23])[N:6]=1)[CH:2]=[CH2:3].Cl.O.[OH-].[Na+]>C(O)C.[Fe]>[CH2:24]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10]([NH2:11])=[C:9]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH3:22])=[C:7]([CH3:23])[N:6]=1)[CH:25]=[CH2:26]
Reactant: C=CCN(CC=C)c1nc(C)c(C)c(NCc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCN(CC=C)c1nc(C)c(C)c(NCc2ccccc2)c1N
Temperature: 70 °C
Yield: 72.2 %

Procedure:
N2,N2-Diallyl-N4-benzyl-5,6-dimethyl-3-nitro-pyridine-2,4-diamine (828 mg, 2.4 mmol) was dissolved in ethanol (15 mL) and 2N HCl (15 mL) and iron powder (527 mg, 9.6 mmol) was added in one portion. The reaction mixture was heated at 70° C. for 2 h, and then cooled to room temperature and poured into 50 mL water. The resulting solution was neutralised with 1N NaOH solution to give a dark green suspension, which was extracted with EtOAc (2×25 mL) and the combined organics were dried over MgSO4, filtered and evaporated to give the title compound as a dark green oil (559 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18](C3C=CC=CN=3)C)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:26]1[CH:31]=[C:30](CN2CCN(C(OC(C)(C)C)=O)CC2)[CH:29]=[N:28][CH:27]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)[CH2:16][CH2:17]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncnc2)CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-(pyrimidin-5-ylmethyl)piperazine-1-carboxylate (1.1 eq, 0.37 mmol, 104 mg), TFA (1.5 mL) and CH2Cl2 (4 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (86 mg, 0.34 mmol) in iPrOH (3 mL) and DIPEA (0.75 mL). Filtration and washing as previously described gave the product (99 mg, 67% for two steps) as a yellow solid; δH (500 MHz, DMSO-d6) 2.54 (s, br, 4H, piperazine N(CH2)2), 3.06 (s, br, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2), 6.97 (s, br, 2H, NH2), 8.16 (s, 1H, bromopyridine H-6), 8.75 (s, 2H, pyrimidine H-4 & H-6), 9.10 (s, 1H, pyrimidine H-2);
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]#[N:13].N1C=CC=CC=1.O>ClCCl>[C:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[NH:6][C:2](=[O:3])[O:4][CH3:5])#[N:13]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccsc1N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1sccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Methyl chloroformate (7.61 g, 80.5 mmol) was added drop-wise to a stirred of 2-amino-3-cyanothiophene (10 g, 80.5 mmol) and pyridine (19.1 g, 242 mmol) in dichloromethane (250 mL) at 0° C. After addition, the mixture was warmed to room temperature and stirred overnight. The reaction was treated with water (50 mL) and extracted with dichloromethane (3×150 mL). The combined organic phase was washed with 1 N hydrochloric acid (2×150 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), and dried over sodium sulfate. It was filtered and concentrated to give a crude product, which was triturated with a solution of methyl tert-butyl ether and petroleum ether (1:1, 50 mL) to give 11 g (75%) of methyl 3-cyanothiophen-2-ylcarbamate as a pale white solid. 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.63-6.65 (d, 1H), 6.94-6.96 (d, 1H), 7.94 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[C@H:10]([F:41])[CH2:9]1)=O)(C)(C)C.[ClH:42].O1CCOCC1>>[ClH:42].[ClH:42].[F:41][C@H:10]1[C@@H:11]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCCCc1nnc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(C(=O)NC[C@H]2CCNC[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
(±)-cis-4-({[6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.47 mmol, 266 mg) was stirred in 4 M HCl/dioxane (2 mL) for 20 min at room temperature. The solvent was evaporated to provide (±)-cis-6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (3-fluoro-piperidin-4-ylmethyl)-amide dihydrochloride. The crude product was used without further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:6]1)=O.[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:6]1)=[O:2]
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 82, Step 5, 0.300 g, 9.31 mmol) is dissolved in 2M methylamine in methanol solution (8 ml) and stirred overnight at room temperature. The resulting precipitate is filtered, washed with methanol, and dried under vacuum to give the title compound as a white solid (0.145 g, 48%), mp 264–5° C.; 1H NMR (300 MHz, CDCl3) δ 2.47–2.52 (m, 2H), 2.64 (d, 3H), 2.84–2.89 (m, 2H), 3.27 (d, 3H), 4.00 (dd, 1H), 4.24 (t, 1H), 5.06 (dd, 1H), 7.26 (s, 1H), 7.46 (dd, 1H), 8.39 (d, 1H); MS for C15H16FN3O4 m/z 322 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[C:23]([F:38])=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[C:23]([F:38])=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:16][C:13]2[NH:12][C:9]4[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=4[C:14]=2[CH3:15])[C:31](=[O:37])[NH:32]3)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2F)N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(-c5cccc(Cl)c5F)c43)c(C)c2C1=O
Yield: 30 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 30.0%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].Cl[CH2:16][CH2:17][O:18]C1CCCCO1>>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH2:16][CH2:17][OH:18])[C:3]1=[O:13]
Reactant: ClCCOC1CCCCO1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)N2
Product: COc1ccc2c(c1)C(C)(C)C(=O)N2CCO

Procedure:
Prepared from 3,3-dimethyl-5-methoxy-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:17](=[O:20])[CH2:18]Cl)=[CH:10][C:11]=3[C:12]2([F:16])[F:15])=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[N:28]1([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35][CH2:18][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3)[C:12]([F:16])([F:15])[C:11]=2[CH:10]=1)=[O:20])=[O:34]
Reactant: O=C(CCl)c1ccc2c(c1)C(F)(F)c1cc(Br)ccc1-2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)C(F)(F)c1cc(Br)ccc1-2
Temperature: 60 °C
Yield: 88.2 %

Procedure:
A mixture of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone (2 g, 5.6 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.32 g, 6.1 mmol), potassium carbonate (1.55 g, 11.1 mmol) and potassium iodide (930 mg, 5.6 mmol) in acetone was heated to 60° C. After forty minutes, the reaction was cooled to room temperature and concentrated. The residue was dissolved in a mixture of ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-2-(2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate (2.65 g, 88%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][C@H:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[O:16]([CH2:15][C@@H:14]([O:23][Si:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:29][CH3:30])[CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:4][C:5]=2[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(COS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (1.93 g) and triethylamine (0.58 ml) in dichloromethane (40 ml) was added dropwise methanesulfonyl chloride (0.27 ml) under ice-cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed successively with water, sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford crude N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-N-(3-methylsulfonyloxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (2.18 g), which was used without purification.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]3[CH:35]=2)=[CH:22][CH:21]=1)[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:7])(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(NC(C)C)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>C(Cl)Cl>[Cl:57][C:58]1[CH:59]=[C:60]([C:6]([NH:8][C@@H:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[N:27]=[C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]4[CH:35]=3)=[CH:24][CH:25]=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])[CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80]
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)nc12
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)O)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61 %

Procedure:
To a solution of 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoate (1.35 g, 2.82 mmol) in CH2Cl2 (14 mL) was added trifluoroacetic acid (10 mL) followed by triethylsilane (2.5 equiv, 7.04 mmol). The reaction was stirred for 45 minutes at room temperature and then concentrated in vacuo. DMF (35 mL) was added to the residue followed by diisopropylamine (14.7 mL, 84.51 mmol) under nitrogen. The reaction was stirred for 5 minutes and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (1.1 equiv, 3.10 mmol) was added. The reaction was stirred for 45 minutes and then concentrated in vacuo. Ethyl acetate (50 mL) was added to the residue and it was washed with H2O (30 mL). The aqueous layer was extracted with EtOAc (20 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 25-100% EtOAc/hexanes) provided the title compound as a white foamy solid (61%). ESMS [M+H]+=520.2.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium bicarbonate, and 100 mg of 3-fluorobenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 120 mg of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.58 (s, 6H), 3.08 (s, 3H), 7.05 (m, 3H), 7.33 (m, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H). IR (cm−1): 3020, 1697, 1620, 1403, 1318, 1149, 958, 768. MS (FAB): 361 (m+1).