Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][S:6]([O-:9])(=O)=[O:7])=[O:4].[Na+].P(Cl)(Cl)([Cl:13])=O>>[CH3:1][O:2][C:3]([CH2:5][S:6]([Cl:13])(=[O:9])=[O:7])=[O:4]
Reactant: COC(=O)CS(=O)(=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Product: COC(=O)CS(=O)(=O)Cl
Yield: 65.7 %

Procedure:
The sodium methoxycarbonylmethylsulfonate salt was added in small portions to a stirred solution of 840 ml (9.14 mols) phosphorus oxychloride. The resulting mixture was then heated at 80°-100° C. for about 5 hours and allowed to cool overnight. The reaction mixture was filtered, the filtered solid was washed with dichloromethane and the filtrate distilled under reduced pressure to remove the dichloromethane and excess phosphorus oxychloride. The resulting oil residue was distilled through a short Vigreaux column to give 226.8 g (65.7% yield) of methoxycarbonylmethylsulfonyl chloride, as a yellow oil, b.p. 79°-80° C. (0.5 mm Hg).
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:10]([CH2:11][CH3:12])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)C(=O)CCC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)C(=O)C(Br)CC
Yield: 98.9 %

Procedure:
The same operation as in Example (106a) was performed using butyl 2-oxopentanoate (described in Cuvigny; C. R. Hebd. Seances Acad. Sci.; 240; 1955; 206, 12 g, 69.8 mmol), bromine (3.33 mL, 65 mmol) and chloroform (80 mL), to obtain 16.15 g of the title compound as a colorless liquid (99%).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][CH2:10][CH:11]([CH3:21])[O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].CCN(C(C)C)C(C)C.N1C=CN=C1>O1CCOCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:9][CH2:10][CH:11]([CH3:21])[O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)Oc1ccccc1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
Tert-butyl-chloro-dimethyl-silane (649 mg; 4.3 mmol; 1.1 eq.) was added to a solution of 2-(2-hydroxy-1-methyl-ethoxy)-benzaldehyde (705 mg; 3.91 mmol; 1 eq.), DIEA (867 μL; 4.69 mmol; 1.2 eq.) and 1H-imidazole (27 mg; 0.39 mmol; 0.1 eq.) in 1,4-dioxane (20 mL) and the resulting mixture was stirred at room temperature for 10 minutes. After dilution with EA, the solution was washed with sat. aq. NH4Cl (3×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (20% to 50% EA in cyclohexane) to afford the title compound (690 mg, 60%) as a colourless oil. 1H NMR (300 MHz, DMSO-d6) δ 10.47-10.33 (m, 1H), 7.72-7.55 (m, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 4.71 (d, J=4.2 Hz, 1H), 3.77 (dd, J=4.8, 2.1 Hz, 2H), 1.28 (d, J=6.2 Hz, 3H), 0.84-0.75 (m, 9H), 0.04-0.07 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[C:15]([CH3:17])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:18][CH2:19][CH3:20])[C:9]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH2:19]([N:18]1[C:10]2[C:9]([CH3:21])=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:16]=[C:15]([CH3:17])[C:11]=2[C:12](=[O:14])[O:13][C:32]1=[O:34])[CH3:20]
Reactant: CCNc1c(C)c(C(=O)OC(C)(C)C)cc(C)c1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCn1c(=O)oc(=O)c2c(C)cc(C(=O)OC(C)(C)C)c(C)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 253.3 %

Procedure:
4-(tert-Butoxycarbonyl)-2-(ethylamino)-3,6-dimethylbenzoic acid (115 mg, 0.392 mmol) was dissolved in tetrahydrofuran (1 mL) and then cooled in an ice bath. N,N-Diisopropylethylamine (0.07 mL, 0.403 mmol) and triphosgene (40 mg, 0.135 mmol) were added, and the mixture was stirred at ambient temperature for 0.5 h. The mixture was quenched with water and extracted with dichloromethane (2×). The combined organic portion was dried over sodium sulfate, then filtered and concentrated to provide tert-butyl 1-ethyl-5,8-dimethyl-2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (109 mg, 0.342 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 4.06 (q, 2H), 2.70 (s, 3H), 2.46 (s, 3H), 1.62 (s, 9H), 1.28 (t, 3H); MS (EI) for C17H21NO5: 320 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.OO.C(=O)([O-])[O-].[Na+].[Na+].[BrH:17]>>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:17])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1cc(N)ncc1Br
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
2-Amino-4-methylpyridine (110 g, 1.02 mol) in hydrobromic acid (1 L, 48%) was stirred at 70° C. and a solution of hydrogen peroxide (300 mL, 15%) was added dropwise over a one h at such a rate that the temperature of the reaction mixture remained at 70-80° C. The mixture was stirred for 90 min at 70° C. and poured onto crushed ice. The pH was adjusted to 4-5 with sodium carbonate and the precipitated solid (containing mostly dibrominated products) was filtered off and discarded. The pH was subsequently raised to 9 and the precipitated product collected by filtration. Recrystallization from toluene gave 2-Amino-5-bromo-4-methylpyridine (76.3 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[C:11]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3F)c(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
While stirring at from 0 to 3°, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are added dropwise to a suspension, cooled to 0°, of 26.6 g of aluminium trichloride in 60 ml of dichloromethane. The whole is stirred for 30 minutes at 0°, 15.9 g of o-fluorobenzoyl chloride are added dropwise thereto and stirring is carried out for 2 hours at from 0° to 3°. The whole is then poured into a mixture of 100 g of ice-water and 5 ml of concentrated hydrochloric acid, extracted by shaking twice with 100 ml of dichloromethane each time, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is taken up in a small amount of dichloromethane, petroleum ether is added until a precipitate begins to form and the whole is then cooled. The precipitate that has formed is filtered off with suction and the filtrate is concentrated by evaporation and chromatographed over silica gel using dichloromethane as eluant. After a small number of first runnings, 4-(o-fluorobenzoyl)-5-methoxybenzocyclobutene-1-carboxylic acid methyl ester is obtained having a melting point of 73°-74°.
Reaction SMILES: N[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1O.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O>>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Product: C1=Cc2ccccc2C1

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride or acetic anhydride. The resulting benzamide or acetamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol or trans-1-acetamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: F[C:2]1C=C(C=CC=1)N.C(C1C=CC(C(O)=O)=CC=1)(=O)C1C=CC=CC=1.C(NCC)C.[F:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:54])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:41]=2)[CH:35]=[CH:36][CH:37]=1.[H-].[Na+]>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([N:38]([CH3:2])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:41]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Nc1cccc(F)c1)c1cccc(C(=O)c2ccccc2)c1
Reactant: Nc1cccc(F)c1
Agent: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CN(C(=O)c1cccc(C(=O)c2ccccc2)c1)c1cccc(F)c1
Reaction time: 0.08 h

Procedure:
Following Procedure A with the substitution of 20 g (88 mmol) 3-benzoylbenzoic acid [579-18-0] and 8.5 mL (88 mmol) 3-fluoroaniline for 4-benzoylbenzoic acid and diethyl amine, the product N-(3-fluorophenyl)-3-benzoylbenzamide was generated (28 g, 88 mmol) as a clear oil. The oil was dissolved in 50 mL dry THF to which a 10 mL THF slurry of 2.1 g (90 mmol) NaH was slowly added. The mixture was allowed to stir for 5 min then 5.6 mL (90 mmol) of Mel was added and continued stirring for 16 h. The reaction was carefully quenched with water and partitioned between water and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered, and concentrated to yield 29.3 g (88 mmol) product. MS m/z (MH+) 334.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:6]([OH:8])[CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[O:8][C:6]=2[CH:7]=1
Reactant: Cc1ccc(-n2cccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Yield: 59.6 %

Procedure:
To 5-methyl-2-pyrrol-1-yl-phenol (6.0 g, 33.6 mmol) in dichloromethane (75 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6.61 g, 33.6 mmol) then trifluoroacetic acid (3.1 mL, 40.3 mmol) and the mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated and the crude residue was purified by column chromatography utilizing a gradient of 0-100% dichloromethane in hexanes to yield tert-butyl 7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (7.1 g, 59%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 6.88 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.29 (t, J=3.2 Hz, 1H), 6.00-5.98 (m, 1H), 5.30 (s, 1H), 3.97 (s, 2H), 3.26 (t, J=12.2 Hz, 2H), 2.32 (s, 3H), 2.09-2.01 (m, 2H), 1.87 (dt, J=13.3, 4.9 Hz, 2H), 1.48 (s, 9H). ESI-MS m/z calc. 354.4. found 355.5 (M+1)+; Retention time 2.28 minutes (3 min run).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][C:5](=[CH:9]O)[C:4]1=[O:11])[CH3:2].[CH2:12]([SH:16])[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:12]([S:16][CH:9]=[C:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:1][CH3:2])[C:4]1=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCC1CCCC(=CO)C1=O
Reactant: CCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCSC=C1CCCC(CC)C1=O

Procedure:
A solution of 2-ethyl-6-(hydroxymethylene)cyclohexanone (43.0 g, 0.277 mole), described in Example 2, butylmercaptan (28.6 g, 0.318 mole) and p-toluenesulfonic acid (50 mg) in dry benzene (200 ml) is heated at reflux under nitrogen for 4 hr using a Dean-Stark water separator. The reaction mixture is cooled and washed with saturated aqueous sodium bicarbonate (50 ml), water and brine, then dried (MgSO4). After removal of the solvent at reduced pressure the residue is distilled to give the title compound, bp 110° - 115° C/1.5 mm, nmr (CDCl3) δ 0.92 (6H), 7.5 (m,1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[CH2:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C1CC(c2ccccc2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 120 °C
Yield: 50.8 %

Procedure:
Pd(PPh3)2Cl2 (40 mg) in a 100 mL of flask under Ar2 was treated sequentially with 6-bromo-4-methylene-2-phenylchroman (200 mg, 0.67 mmol) in [1,4]dioxane (20 mL), Cs2CO3 (2 N, 3.33 mL) and 3-cyanophenylboronic acid (167 mg, 1.13 mmol). The mixture was heated under 120° C. at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (110 mg, 51%). 1H-NMR (CDCl3): 2.81 (m, 2H), 4.96 (d, 1H), 5.10 (m, 1H), 5.61 (d, 1H), 7.98 (d, 1H), 7.29 (m, 1H), 7.35 (m, 3H), 7.41 (m, 2H), 7.46 (m, 1H), 7.52 (m, 1H), 7.72 (m, 2H), 7.79 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2I)[CH2:17][CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:18]=3[CH:15]3[CH2:17][CH2:16]3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: Ic1cnccc1C1CC1
Reactant: COc1cc2c(cc1Cl)C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C1CC1)CC2
Yield: 22.5 %

Procedure:
7-Chloro-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 100 mg, 0.473 mmol) was reacted with 4-cyclopropyl-3-iodopyridine (I-73c: 127.6 mg, 0.521 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.047 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.7 mg, 0.047 mmol) and potassium phosphate (301.6 mg, 1.421 mmol) for 12 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afford 35 mg of the product
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:16]=1)=[C:6]1[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@H:8]([CH2:14]Cl)[O:7]1.[NH:17]1[CH2:22][CH:21]=[C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1>CS(C)=O.C(OCC)(=O)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:20]2[CH2:21][CH2:22][N:17]([CH2:14][CH:8]3[O:7][C:6]4[C:11](=[CH:12][CH:13]=[C:4]5[NH:3][C:2]([CH3:1])=[N:16][C:5]5=4)[O:10][CH2:9]3)[CH2:18][CH:19]=2)=[CH:24]1
Reactant: Cc1nc2c3c(ccc2[nH]1)OC[C@H](CCl)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 105 °C

Procedure:
A mixture of 0.50 g (2.1 mmole) of [(8R)-2-methyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl chloride and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 100-110° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give the desired compound as the free base. Recrystallization from ethanol with the addition of 0.12 g of fumaric acid gave 0.11 g of the (S)-enantiomer of the title compound as a yellow solid fumarate, one-quarter hydrate, m.p. 219-222° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1)C>C1(C)C=CC=CC=1>[CH3:23][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:35])[CH:28]=1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-isocyanato-benzoic acid ethyl ester ([41221-47-0]) in toluene for 72 h under reflux conditions to give the title compound as yellow oil. MS: m/e=469.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: Cc1cc(C2(C(=O)O)CC2)on1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)on1
Temperature: 40 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.24 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (86 mg, 0.24 mmol), and diisopropylethylamine (200 μL, 1.2 mmol) were combined and dissolved in N,N-dimethylformamide (1.25 mL). O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (109 mg, 0.287 mmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (56 mg, 53%). MS (ES+) (M+H) 439.2; LCMS retention time 1.94 min (Method L).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[N:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Cl:19])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:27](=[O:29])[CH3:28].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:10]=[C:8]([C:6]1[N:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[CH:4][CH:5]=1)[CH3:9]
Reactant: CC(=O)N(C)C
Reactant: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2.00 g (0.0059 mol) of [1-(6-bromopyridin-2-yl)ethylidene](2-chloro-4,6-dimethylphenyl)amine were dissolved in 25 ml of diethyl ether and cooled to −70° C. 3.70 ml (0.0059 mol) of a 1.6 M solution of butyllithium in hexane were added dropwise over a period of 15 minutes. The temperature rose to −40° C. and the mixture was stirred for another 30 minutes. The mixture was cooled to −70° C. and 0.52 g (0.0059 mol) of N,N-dimethylacetamide was added dropwise and the mixture was stirred at room temperature for another three hours. The reaction mixture was stirred with 5 ml of a saturated ammonium chloride solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over Na2SO4, filtered and the solvent was distilled off under reduced pressure. This gave 0.83 g (0.0028 mol) of the product in a yield of 47%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(CCc1cccs1)[C@H]1CCc2cccc(O)c2C1

Procedure:
Synthesis worked according to the preparation of A7-1 when using 76 mg (0.23 mmol) (S)-N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine ((S)-A5-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using hexane/ethyl acetate 10/1 in the presence of 1% (v/v) of dimethylethylamine to achieve compound 1b.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C@@H:13]3[CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][C@H:32]2[NH:34][CH2:35][C@@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][N:34]3[CH2:35][CH:27]4[N:26]([C:17]5[CH:18]=[CH:19][C:20]6[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH:16]=5)[CH2:33][CH:32]3[CH2:31][CH:30]=[CH:29][CH2:28]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2c(OC[C@@H]3CO3)cccc21
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ccc2c(OC[C@@H](O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cccc21
Temperature: 120 °C

Procedure:
(S)-1-Methyl-4-oxiranylmethoxy-1H-indole (50 mg, 0.25 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (50 mg, 0.189 mmol) were placed in a μW tube with ethanol (2 ml), DIPEA (100 μL, 0.576 mmol) and heated to 120° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via flash chromatography (gradient 30% to 100% ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: O1[CH2:5][CH2:4][NH:3]C1=O.[ClH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(O)C>C(OCC)C>[ClH:7].[F:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:5][CH2:4][NH2:3])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1NCCO1
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NCCNc1cccc(F)c1
Temperature: 165 °C
Reaction time: 18 h

Procedure:
Equimolar quantities (45.7 mmol) of 2-oxazolidinone and 3-fluoroaniline hydrochloride were combined, heated to 165° C., and stirred for 18 hours. The dark-colored mixture was allowed to cool to ambient temperature and treated with ethanol (125 mL). The suspension was heated to reflux for 1 hour, allowed to cool to ambient temperature, treated with diethyl ether (125 mL), and the suspension was cooled to 0° C. for 2 hours. Filtration provided 5.53 g of the desired product as colorless crystals which were used without further purification.