Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:64][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[CH:64][CH:63]=3)[C:57]([O:59][CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The methyl (2S)-2-amino-3-biphenyl-4-ylpropanoate (36 mg, 0.14 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (5 mg, 10%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=525.1.
Reaction SMILES: [Br:1]Br.II.[C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].O>C(O)(=O)C>[Br:1][CH2:9][C:7](=[O:8])[CH2:6][C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
Under a nitrogen atmosphere, a solution of bromine (1.16 ml, 22.59 mmol) in 17 ml of acetic acid containing a small crystal of iodine was added over 2.5 hours to a solution of acetoacetanilide (4.0 g, 22.57 mmol) in 12 ml of acetic acid, at room temperature (cooling with cold water). The reaction mixture was stirred at room temperature for 3 hours, then poured into 100 ml of ice-cold water and the crude solid product was filtered off. Following crystallization from ethanol, 3.30 g of 4-bromoacetoacetanilide were obtained, m.p 130°-132° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10].C(O)(C)C>O>[CH2:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:9]([CH3:10])[CH3:8]
Reactant: C=CC
Reactant: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)Cc1ccccc1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
A 1-L Parr autoclave provided with a high shear turbine-type impeller was charged with 4.3g of NaK (an alloy having a K content of 78% by weight) and 428g of toluene. The mixture was heated to 160° C. under normal agitation, i.e., an agitator tip speed of 1.5 m/sec.; and the agitator tip speed was then increased to 5.7 m/sec. The mixture was agitated at this speed for 15 minutes, after which the temperature was increased to 190° C. Then 160 g of propene was fed over a period of 30 minutes while the temperature was maintained below 200° C. with cooling and the pressure below 2.8 MPa by regulating the propene feed rate. The autoclave was kept at 190° C. for one hour, and agitation was then slowed to normal. The NaK was deactivated by the addition of 12 g of isopropanol and 142 g of water. Analysis of the organic phase by gas chromatography showed that the reaction resulted in conversion to isobutylbenzene at the rate of 0.975 mol/hr. This compares with a conversion rate of only about 0.75 mol/hr. when diatomaceous earth- or potassium carbonate-supported NaK is employed as the catalyst and normal agitation conditions are maintained throughout the reaction.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[I:8][C:3]1[CH:4]=[CH:5][C:6]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:7][CH:2]=1
Reactant: Ic1ccccc1I
Reactant: CCCCSCCCC
Product: CCCCSc1ccc(I)cc1

Procedure:
The general procedure was used to convert diiodobenzene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a pale yellow oil (512 mg, 88% yield). 1H NMR (300 MHz, CDCl3) δ 7.58–7.55 (d, J=8.4, 2H; Ha, Ha′), 7.05–7.02 (d, J=8.2, 2H; Hb, Hb′), 2.91–2.86 (t, J=7.3, 2H; Hc), 1.67–1.49 (m, 2H; Hd), 1.42–1.30 (m, 2H; He), 0.94–0.89 (t, J=7.3, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 137.6 (C1, C1′), 137.2 (C4), 130.2 (C2, C2′), 90.0 (C3), 32.9 (C5), 30.9 (C6), 21.9 (C7), 13.6 (C8). High Resolution Mass. Spec. for C10H13S; Expected, 291.9783; Found, 291.9796
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H](CCl)COc1ccccc1Br
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-bromophenyl(2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[C:32]5[CH:33]=[CH:34][N:35]=[C:36]([Cl:37])[C:31]=5[N:30]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:28]=4[N:29]=3)=[N:21][CH:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl>CO>[Cl:37][C:36]1[C:31]2[N:30]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:28]3[N:29]=[C:24]([NH:23][C:20]4[N:21]=[CH:22][C:17]([N:14]5[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[N:25]=[CH:26][C:27]=3[C:32]=2[CH:33]=[CH:34][N:35]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: CO
Product: OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Compound 217 (0.094 g, 0.15 mmol) was combined with 10 mL of methanol and 4 mL of 1N HCl. The solution was stirred at room temperature overnight. The solution was concentrated under vacuum and the residue obtained was purified on CombiFlash column (dry loaded), eluting with a gradient of 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 10% methanol/0.5% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum to give a yellow solid. The solid was partially dissolved in methanol and then collected on filter paper. Washed the solid off of the filter paper with DCM/methanol through a fritted funnel and then concentrated under vacuum to give compound 213 (0.065 g, 85% yield) as a yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ 9.92 (1 H, s), 9.33 (1 H, s), 8.22 (1 H, d, J=5.1 Hz), 8.10 (1 H, d, J=4.9 Hz), 8.04 (1 H, d, J=2.9 Hz), 8.02 (1 H, d, J=9.0 Hz), 7.46 (1 H, dd, J=9.0, 2.9 Hz), 5.95-6.05 (1 H, m), 4.43 (1 H, t, J=5.4 Hz), 3.54 (2 H, q, J=6.1 Hz), 3.12-3.19 (4 H, m), 2.55-2.65 (6 H, m), 2.45 (2 H, t, J=6.4 Hz), 1.98-2.08 (4 H, m), 1.65-1.75 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 493.1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[N:12]1([CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([O:20][CH2:19][CH2:18][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: N#Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1

Procedure:
Compound is prepared from 4-cyanobenzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 213-214° C.; 1H NMR (300 MHz, CDCl3) δ 2.70 (m, 4H), 3.00 (t, 2H), 3.78 (t, 4H), 4.35 (t, 2H), 6.80 (d, 1H), 7.50-7.70 (m, 5H), 7.80 (d, 1H), 7.95 (d, 2H), 8.31 (s, 2H); MS 402 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([C:22]3[CH:23]=[C:24]([C:29]4[CH:34]=[C:33]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)[N:32]=[CH:31][C:30]=4[NH2:41])[C:25](F)=[N:26][CH:27]=3)=[CH:21][C:15]=2[CH2:14]1)[CH3:12]>C1COCC1>[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([C:22]3[CH:27]=[N:26][C:25]4[NH:41][C:30]5[CH:31]=[N:32][C:33]([C:35]6[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=6)=[CH:34][C:29]=5[C:24]=4[CH:23]=3)=[CH:21][C:15]=2[CH2:14]1)[CH3:12]
Reactant: CCN1CCc2sc(-c3cnc(F)c(-c4cc(-c5cnn(C)c5)ncc4N)c3)cc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2sc(-c3cnc4[nH]c5cnc(-c6cnn(C)c6)cc5c4c3)cc2C1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1N solution in THF, 4.5 mL, 4.5 mmol) was added dropwise over 10 minutes to a solution of 5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4]bipyridinyl-3′-ylamine (638 mg, 1.50 mmol) in anhydrous THF (26 mL). After 30 minutes, the reaction was quenched by the addition of aqueous saturated aqueous potassium fluoride solution (10 mL). The resultant brown solution was partitioned between DCM (75 mL) and brine (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (96 mg, 16%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.82 (s, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 4.00 (s, 3H), 3.64 (s, 2H), 3.02-2.95 (m, 2H), 2.93-2.86 (m, 2H), 2.70 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: B#B.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:25](=[CH:26][CH:27]=1)[C:11]1=[C:12]([CH2:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=O)[C:13](=[O:17])[NH:14][CH2:15][CH2:16][CH:10]1[CH2:9][CH2:8]2.Cl>O1CCCC1>[CH:22]([NH:21][CH2:19][CH2:18][C:12]1[C:13](=[O:17])[NH:14][CH2:15][CH2:16][CH:10]2[CH2:9][CH2:8][C:7]3[C:25](=[CH:26][CH:27]=[C:5]([O:4][CH3:3])[CH:6]=3)[C:11]=12)([CH3:23])[CH3:24]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(=O)NC(C)C)=C21
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CCNC(C)C)=C21

Procedure:
80 ml of 1 M diborane in tetrahydrofuran are added to the suspension of 6.8 g of [9-methoxy-2-oxo-3,4,5,5a,6,7-hexahydro-2H-naphth-[1,2-d]azepin-1-yl]-N-isopropyl-acetamide in 100 ml of tetrahydrofuran while stirring under nitrogen at 0°. After 20 hours 60 ml of 3 N hydrochloric acid are added dropwise and the mixture is refluxed for one hour. The tetrahydrofuran is distilled off under reduced pressure and the remainder is diluted with water. The resulting precipitate is filtered off and re-extracted with hot water. The aqueous filtrate is washed with diethyl ether and basified with 3 N aqueous sodium hydroxide. The suspension is extracted with methylene chloride, the extract dried, evaporated and the residue recrystallized from acetone, to yield the 1-(2-isopropylaminoethyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 147°-149°.
Reaction SMILES: C1COCC1.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:26]=4)[CH2:17][CH2:16]3)=[CH:12][CH:13]=[CH:14][C:7]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([CH2:31][OH:32])[CH:26]=4)[CH2:19][CH2:20]3)=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: Cn1nc(CO[Si](C)(C)C(C)(C)C)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nc(CO)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
A THF solution (8 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-(tert-butyl-dimethylsilanyloxymethyl)-1-methyl-1H-pyrazole (0.75 g, 1.5 mmol) was cooled on ice and a 1M THF solution of tetrabutyl ammonium fluoride (1.7 ml) was added thereto. The mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=1:0→30:1→15:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate and diisopropyl ether to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-3-hydroxymethyl-1-methyl-1H-pyrazole (0.46 g, 79% yield) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[NH:23][C:22]4=[O:29])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH:31]([CH3:35])[C:32](=[O:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[N:23]([CH:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:22]4=[O:29])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(N4C(=O)NC(C)(C)C4=O)cc3)CC2)cc1
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)N(C(C)C(C)=O)C(C)(C)C4=O)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
A mixture of 21.3 parts of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-2,4-imidazolidinedione, 7.5 parts of 3-chloro-2-butanone, 6.0 parts of potassium carbonate and 180 parts of N,N-dimethylformamide was stirred overnight at 100° C. After cooling, the reaction mixture was diluted with 700 parts of water. The crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. After trituration of the residue in methanol, the product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 7.77 parts (30.9%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-1-(1-methyl-2-oxopropyl)-2,4-imidazolidinedione; mp. 225.9° C. (intermediate 20).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32](=[CH2:38])[CH2:33][O:34][C:35](Cl)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:26][CH2:27][N:28]([C:35]([O:34][CH2:33][C:32]([CH3:38])=[CH2:31])=[O:36])[CH2:29][CH2:30]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)c2c(N3CCNCC3)n(-c3ccccc3)c3ccccc23)CC1
Reactant: C=C(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)COC(=O)N1CCN(c2c(C(=O)N3CCN(C)CC3)c3ccccc3n2-c2ccccc2)CC1
Yield: 94 %

Procedure:
Reaction in analogy to Example 60 from 1-phenyl-2-(1-piperazinyl)-indole-3-carboxylic acid-4-methyl-piperazide and chloroformic acid-2-methyl-2-propenyl ester. After working up with methylene chloride and heated sodium carbonate solution, the crystalline residue of the organic phase was triturated with ether, suction-filtered and washed with ether. Melting point: 141°-143° C., yield: 94% of the theory.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[C:9](=[O:19])[N:10]3C(C4C=CC=CC=4)[O:12][C:3]=1[C:4]=23.[CH2:26](O)[CH3:27]>>[CH2:26]([O:19][CH:9]1[CH:8]2[CH2:20][CH2:21][CH2:22][N:7]2[C:6](=[O:23])[C:5]2[CH:24]=[CH:25][C:2]([CH3:1])=[C:3]([OH:12])[C:4]=2[NH:10]1)[CH3:27]
Reactant: CCO
Reactant: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Product: CCOC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Temperature: -20 °C
Reaction time: 72 h

Procedure:
350 mg of 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo(5,4,3-jk)pyrrolo(2,1-C)(1,4)benzodiazepin-6,11-dione was treated in the same manner as in Example 4. The concentrate of the chloroform layer obtained was dissolved in 2 ml of hot ethanol, cooled to -20° C., and allowed to stand at this temperature for 3 days. Thus, 86 mg of 2,3,5,10,11,11a-hexahydro-11-ethoxy-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained in a colorless crystalline form. Recrystallization of the resulting product from ethanol gave a colorless needle-like crystal having a melting point of 155° to 157° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14](O)=[O:15])[N:7]=3.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:21])=[O:15])[N:7]=3
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (8.27 g, 26.7 mmol), EDCI (6.66 g, 34.8 mmol), HOBt (4.69 g, 34.8 mmol) and ammonium chloride (4.29 g, 80.2 mmol) in DMF (80 mL) was added triethylamine (7.49 mL, 53.5 mmol) and the reaction mixture stirred at 45° C. for 1.5 h. The reaction mixture was concentrated in vacuo and the residue triturated with water (250 mL). The precipitated product was collected by filtration and dried in vacuo at 45° C. for 16 h to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a buff coloured solid (7.67 g, 93%). 1H NMR (400 MHz, d6-DMSO) 8.40 (1H, d, J=8.7 Hz), 7.80 (1H, s), 7.42 (1H, br s), 7.32 (1H, dd, J=8.7, 2.0 Hz), 7.27 (1H, d, J=2.1 Hz), 7.15 (1H, br s), 4.50-4.46 (4H, m). LCMS: RT=3.07 min, M+H+=308/310. 1H NMR showed product to contain 5% 8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:20]([O-])=[O:21].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[N:10]([N:20]=[O:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-6-methyl-1,2,3,4-tetrahydroquinoline (0.28 g, 0.00166 mol) in ethanol (1 mL) was added 1N hydrochloric acid (1 mL), and the reaction mixture was cooled to 0° C. Sodium nitrite (0.160 g, 0.00232 mol) in water (3 mL) was added at 0° C., and the mixture stirred for 1 h at RT. The reaction was monitored by TLC. After completion, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.28 g, 89% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=1)=C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)=[O:35])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-m-tolylurea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 1-isocyanato-3-methylbenzene (22.3 mg, 0.17 mmol) according to General Procedure G to give 20 mg (27.7%) of a white solid. Anal. Calcd. for C26H33N5O m/z 431.3, found: 432.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.20 (s, 2H), 7.10 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 6.71 (d, J=7.4 Hz, 1H), 6.15 (d, J=7.6 Hz, 1H), 3.89 (d, J=11.1 Hz, 1H), 3.77 (d, J=13.2 Hz, 1H), 3.26 (d, J=8.9 Hz, 1H), 2.79 (m, 1H), 2.57 (m, 1H), 2.42 (m, 1H), 2.24 (s, 1H), 1.88 (m, 3H), 1.65 (m, 4H), 1.45 (m, 1H), 1.21 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.Cl.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C(O)CCC>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(Br)cc1
Reactant: C=C(OCC)c1c(C)nc(C)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: C=C(OCC)c1c(C)nc(C)nc1NCc1ccc(Br)cc1
Yield: 55.6 %

Procedure:
A mixture of 4-chloro-2,6-dimethyl-5-(1-ethoxyvinyl)pyrimidine (3.00 g, 0.0141 mol), 4-bromobenzylamine hydrochloride (3.45 g, 0.0155 mol), NaHCO3 (2.37 g, 0.0282 mol), and n-butanol (20 mL) was heated under reflux for 70 h. The mixture was concentrated, taken up in EtOAc, washed with water, dried MgSO4), and concentrated. Trituration with ether/hexane gave 2.84 g (56%) of product as a white solid. An analytical sample was recrystallized from ether/hexane, mp 111°-113° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH3:16])[C:6]1=[O:7])[CH3:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25]>>[CH3:1][O:2][CH:3]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[CH:11]=[N:10][C:9]=2[N:8]([CH3:16])[C:6]1=[O:7])[CH3:4]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: COC(C)n1c(=O)c2[nH]cnc2n(C)c1=O
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(C(C)OC)c(=O)n2C)OCC

Procedure:
The title substance was prepared from 1-methoxyethyl-3-methylxanthine and diethyl 4-chlorobutanephosphonate analogously to Example 4 and crystallized from diisopropyl ether.