Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCCCCCCCC.Br[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2.[C@@H]1(N)CCCC[C@H]1N.[CH3:32][O:33][C:34]([C:36]1[CH:40]=[CH:39][NH:38][CH:37]=1)=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:32][O:33][C:34]([C:36]1[CH:40]=[CH:39][N:38]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:37]=1)=[O:35]
Reactant: COC(=O)c1cc[nH]c1
Reactant: Brc1cccc2cccnc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: COC(=O)c1ccn(-c2cccc3cccnc23)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 124.1 %

Procedure:
20 mL of 1,4-dioxane, 0.32 mL of n-dodecane, 1.5 g (7.21 mmol) of 8-bromoquinoline and 0.77 mL (6.41 mmol) of trans-1,2-cyclohexanediamine are added at a temperature in the region of 22° C. under an argon atmosphere to 0.8 g (6.39 mmol) of 3-methoxycarbonyl-1H-pyrrole, 3 g (14.13 mmol) of potassium orthophosphate and 0.09 g (0.47 mmol) of copper iodide. After stirring at a temperature in the region of 100° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is diluted with 100 mL of ethyl acetate and the solution obtained is washed with twice 100 mL of water and then with 25 mL of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 2 g of a brown oil which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (80/20 by volume)]. After concentrating the fractions under reduced pressure, 0.8 g of a 1/1 (evaluated by NMR) mixture of 3-methoxycarbonyl-1-(quinol-8-yl)-1H-pyrrole and of 8-bromoquinoline is obtained, which mixture is used without further purifications in the following step.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([CH2:14][CH2:15][CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[OH-].[Na+]>CO.O>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][S:17][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:4]([OH:37])=[O:3])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
To a solution of the compound of example 28 (3.00 g, 5.78 mmol) in methanol (30 mL) and water (10 mL) was added NaOH (1N, 11.6 mL, 11.6 mmol). The mixture was stirred vigorously under ambient conditions. After 24 hours, most of the methanol has evaporated. The residue was portioned between water and ether. The water phase was extracted two times with ether, then acidified with HCl (1N) to pH 1. The water phase was extracted three times with ethyl acetate. The recombined organic phase was dried over sodium sulfate, filtered, and evaporated. The residue was flashed using 5% methanol in chloroform to give the product as a white solid. 1H-NMR(CDCl3, 400 MHz: 1.45(s, 9H); 1.35-1.64(m, 4H); 1.58(m, 1H); 2.16(m, 2H); 2.26(m, 1H); 2.64(m, 1H); 4.12(q, J=7.1 Hz, 2H), 7.19-7.29, 7.40(m, 15H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.Br.Br.[CH2:45]([C:47]1[C:48]([C:55]2[CH:63]=[C:62]3[C:58]([C:59]([C:64]4[NH:65][C:66]5[CH2:71][CH2:70][NH:69][CH2:68][C:67]=5[N:72]=4)=[N:60][NH:61]3)=[CH:57][CH:56]=2)=[CH:49][C:50]([F:54])=[C:51]([OH:53])[CH:52]=1)[CH3:46].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:45]([C:47]1[CH:52]=[C:51]([OH:53])[C:50]([F:54])=[CH:49][C:48]=1[C:55]1[CH:63]=[C:62]2[C:58]([C:59]([C:64]3[NH:65][C:66]4[CH2:71][CH2:70][N:69]([C:11]([C:8]5[CH:7]=[N:6][C:5]([O:4][C:3]6[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=6[F:1])=[CH:10][N:9]=5)=[O:13])[CH2:68][C:67]=4[N:72]=3)=[N:60][NH:61]2)=[CH:57][CH:56]=1)[CH3:46]
Reactant: O=C(O)c1cnc(Oc2ccccc2F)cn1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[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: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Oc5ccccc5F)cn3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a solution of 5-(2-fluoro-phenoxy)-pyrazine-2-carboxylic acid (Preparation 45, 19 mg, 80 μmol) in DMF (1 mL) was added HBTU (32 mg, 85 μmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. 5-Ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and DIPEA (56 μL, 320 μmol) were added and stirring was continued at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method B to afford 8.3 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[N+]([O-])=O.[CH3:14][O-:15].[Na+].S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: C[O-]
Reactant: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
4.5 g (25 mmol) of 3-methoxy-2-methyl-4-nitropyridine 1-oxide are stirred at 40° C. in 75 ml of dry methanol, after addition of 4.7 ml of 30% strength sodium methylate solution, for 16 hours. The mixture is then cooled, brought to pH 7 with concentrated sulphuric acid, filtered and concentrated completely in vacuo, the oily, reddish residue is taken up in 50 ml of toluene, the mixture is filtered again to remove insoluble constituents and the filtrate is concentrated to dryness. The yellow oily residue crystallises in an ice-bath and is finally extracted by stirring with 30 ml of petroleum ether (50/70) at 40° C. Filtration and drying in a desiccator gives 5.2 g (88% of theory) of 3,4-dimethoxy-2-methylpyridine 1-oxide in the form of pale yellow crystals of m.p. 111°-113° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c7) the title compound is obtained as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1.[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=O.Cl>>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][OH:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2ccc(-c3cccc(N4CCNCC4)n3)cc21
Reactant: O=CCCCCO
Agent: Cl
Product: CC1(C)CCc2ccc(-c3cccc(N4CCN(CCCCCO)CC4)n3)cc21

Procedure:
The preparation is carried out analogously to FS501 starting from 144 mg (0.47 mmol) of 1-[6-(3,3-dimethylindan-5-yl)pyridin-2-yl]piperazine and 96 mg (0.94 mmol) of 5-hydroxypentanal. The product is the hydrochloride.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C(#N)CCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)=[O:26]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCCCCBr
Solvent: CCCC#N
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Temperature: 20 °C
Reaction time: 22 h

Procedure:
Pyridine (1.6 mL, 1.1 equivalents) is added to a mixture of 4-aminobenzamide (2.5 g, 18 mmol) and n-butyronitrile (65 mL) at 20° C. under an atmosphere of nitrogen. The mixture is stirred for 15 minutes before a solution of 8-bromooctanoyl chloride (3.7M in toluene, 5.5 mL, 20 mmol, 1.1 equivalents) in n-butyronitrile (10 mL) is added over 20 minutes. The mixture is then stirred at 20° C. for 22 hours. Upon complete reaction the mixture is filtered. The resulting product is washed with methanol (10 mL), water (2×25 mL), methanol (10 mL) and tert-butyl methyl ether (TBME, 10 mL) before being dried in vacuo to yield the title compound, generally as a solid.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:33][CH2:32][N:31]3[C@@H:26]([CH2:27][O:28][CH2:29][CH2:30]3)[CH2:25]2)[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl.O1CCOCC1>CO>[Cl:34][C:19]1[N:20]=[C:21]([N:24]2[CH2:33][CH2:32][N:31]3[C@@H:26]([CH2:27][O:28][CH2:29][CH2:30]3)[CH2:25]2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NNc1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Reaction time: 72 h
Yield: 64.7 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (4.34 g, 7.20 mmol) in MeOH (18 mL) was added 4 N HCl in dioxane (18 mL, 72 mmol). The solution was stirred for 3 days, and then concentrated in vacuo. The residue was dissolved in water (50 mL) and the solution was adjusted to pH 10 with 20% aq. K2CO3. The mixture was extracted with DCM (2×100 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (9aR)-8-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (1.41 g, 65%) as an orange solid. LCMS: (M+H)+: 303.1.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25]1(=[O:39])[N:29]([CH2:30][CH2:31][C:32]#[CH:33])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12>CN(C)C=O.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>[C:28]1(=[O:34])[N:29]([CH2:30][CH2:31][C:32]#[C:33][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:25](=[O:39])[C:26]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:27]12
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.8 %

Procedure:
5-Iodo-2′-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yne (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles.
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH:11][CH3:12])[C:3]=1[C:4]#[N:5].O.NN>C(O)C.[Ni]>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([CH3:10])=[CH:7][C:6]=1[NH:11][CH3:12]
Reactant: CNc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1cc(C)nc(O)c1CN
Temperature: 55 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
2-hydroxy-6-methyl-4-(methylamino)nicotinonitrile (163 mg, 1.0 mmol) was dissolved in ethanol (10 mL) and was warmed to 55° C. before it was treated with Raney nickel (0.5 mL slurry in water) followed by addition of hydrazine monohydrate (2 mL). The resulting mixture was allowed to stir at 55° C. for 2 hours. The cooled reaction mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 3-(aminomethyl)-6-methyl-4-(methylamino)pyridin-2-ol (60 mg, 36% yield) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.I[CH3:11]>C(#N)C.C(N(C(C)C)CC)(C)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 4-methoxy-aniline (0.65 g, 5.28 mmol) and iodomethane (0.33 mL, 5.28 mmol) in Acetonitrile (10.0 mL), diisopropylethylamine was added (1.50 mL, 10.56 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and the crude product 6a was used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCCCCC.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[CH3:9])=[C:4]([Sn:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1[Sn](C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-chloro N-pivaloylaniline* (2.11 g, 10 mmol) in 30 ml of dry THF was cooled in an ice bath under an atmosphere of nitrogen. Then an hexane solution of 1.6M of n-Buli (15.625 ml, 25 mmol) was added dropwise. After stirring at 0° C. for 2.5 h, trimethyltin chloride (2.19 g, 11 mmol) dissolved in dry THF (8 ml) was added within 20 min at 0° C. The reaction was then stirred for 2 h at 0° C. and for 16 h at room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (di-isopropylether: petroleum ether 40°/70°=10:23) to yield 4-chloro-2-trimethylstannyl-N-pivaloylaniline as a white solid 3.1 g; 82.9%; m.p. 169°-172° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(N3CCOCC3=O)cc2F)C1)c1ccc(Cl)s1

Procedure:
72.2 Using general method H. 5-chloro-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide. White solid. MS 481.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]3[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[Cl:37])=[CH:21][CH:20]=2)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([CH3:38])[CH:3]=1.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:45]=1B(O)O.C(COC)OC.O.[OH-].[Ba+2].[OH-]>O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:13]([O:12][C:11](=[O:17])[NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:45]2[C:46]([CH3:50])=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[CH:3][C:4]=1[CH3:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]2[C:30]([Cl:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=2[Cl:35])=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(Br)cc3C)cc2)c(Cl)c1
Reactant: COCCCc1cccc(C)c1B(O)O
Agent: [Pd]
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COCCCc1cccc(C)c1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution tert-butyl (2-(4-bromo-2-methylphenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from EXAMPLE 2, step 2 (1 eq.) and [2-(3-methoxypropyl)-6-methylphenyl]boronic acid from step 1 (1.1 eq.) in 1-2 dimethoxyethane/water (6/1; 0.1M) at room temperature was added palladium tetrakis(triphenylphosphine) (0.05 eq.) and Barium hydroxide (1.5 eq.). The mixture was stiffed at 80° C. for 5 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 70%, in 30 min) afforded the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].OS(O)(=O)=O.[CH3:20]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:20])=[O:13]
Reactant: CO
Reactant: O=C(O)c1cccc2c(Br)cccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Yield: 92 %

Procedure:
To a suspension of 5-bromo-1-naphthylcarboxylic acid (5 g, 20 mmol) in 200 mL anhydrous MeOH was added 5 mL concentrated H2SO4 and refluxed overnight. The reaction was cooled to room temperature and concentrated to one-third the volume. The residue was diluted with water and extracted with diethyl ether. The organic layer was separated and washed with water (2×), dried over MgSO4, and concentrated. Silica gel column chromatography using hexane/ethyl acetate (2/11) gave 4.91 g (92%) of the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A suspension of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (6.08 g, 0.0212 mol) in 6 M hydrochloric acid was refluxed for 22 hours and cooled to room temperature. The solids were filtered and washed with 0.1 M hydrochloric acid. The filter cake was dried under house vacuum (air bleed) to give 5.72 g of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid as a peach colored solid; mp 173.5-175.5° C.
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:7][NH:8]2)(O)=O.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Cl:13][C:10]1[C:9]2[NH:8][CH:7]=[C:6]3[CH2:14][CH2:15][C:16](=[O:18])[C:4]([C:5]=23)=[CH:12][CH:11]=1
Reactant: O=C(O)CCc1c[nH]c2c(Cl)ccc(C(=O)O)c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2c[nH]c3c(Cl)ccc1c23

Procedure:
A mixture of 4-carboxy-7-chlorindole-3-propionic acid (40 g, 0.15 mole), acetic anhydride (320 ml), and anhydrous sodium acetate (3.0 g) is stirred and heated at reflux for 18 hours in the dark. The reaction mixture is cooled and then the solvent is removed under vacuum. The residue is taken up in ethanol (180 ml) and sodium hydroxide 10% (155 ml) is added slowly keeping the temperature below 45° C. After stirring for 1 hour at ambient temperature most of the ethanol is removed in vacuo and the solid that separates is recovered by filtration and dried. The yield of 8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one is 9.1 g (30%) melting 175°-180° C. (dec). The pure compound, is crystalized from toluene and melts 185°-187° C. (dec.). ##STR14##
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(-c2ccncc2)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(-c3ccncc3)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-pyridin-4-ylphenol (J. Heterocycl. Chem. 1991, 28, 933): 1H-NMR (CDCl3) δ 8.69 (2H, dd, J=4.4, 1.6 Hz), 8.57 (1H, d, J=2.8 Hz), 8.15 (1H, d, J=2.6 Hz), 8.12 (1H, br.s), 8.00 (2H, dd, J=6.8, 1.9 Hz), 7.61–7.42 (7H, m), 7.27–7.22 (1H, m), 5.45–5.34 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.9 Hz); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10].Cl.Cl[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:21][CH2:22][N:23]([CH:31]([CH3:32])[CH3:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10]
Reactant: N#CC(CCN1CCCCC1)c1ccccc1Cl
Reactant: CC(C)N(CCCl)Cc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)Cc1ccccc1

Procedure:
alkylating α-(2-chlorophenyl)-1-piperidine butanenitrile with N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in the presence of base and dimethyl sulfoxide to give α-(2-chlorophenyl)-α-[2-[(1-methylethyl) (phenylmethyl)amino]ethyl]-1-piperidinebutane nitrile;