Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][CH:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:4]=1.[C:22](Cl)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C:3]1[S:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][CH:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:4]=1)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: OCc1cc2c(s1)-c1ccccc1OC2c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCc1cc2c(s1)-c1ccccc1OC2c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5.9 g 4H-2-hydroxymethyl-4-phenyl-thieno[3,2-c][1]benzopyran and 5.8 g of palmitoyl chloride in 50 ml pyridine is stirred at room temperature for 4 h. After filtration, one adds 400 ml water to the filtrate. The precipitate which appears is collected. This material is dissolved in methylene chloride and this organic phase is washed with hydrochloric acid solution, then with water, dried and evaporated. The residue is purified by column chromatography on silicagel using a mixture of n-hexane and methylene chloride as eluant. Pure 4H-2-palmitoyloxymethyl-4-phenyl-thieno[3,2-c][1]benzopyran is obtained as a white powder; m.p. 64°-65° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][N:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCC3(CCN(Cc4ccccc4)C3)C2)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-benzyl-2,7-diazaspiro[4.4]nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 momol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.74 (s, 3H), 3.13 (br s, 4H), 2.89 (t, J=7.3 Hz, 2H), 2.72 (AB, J=7.6 Hz, 2H), 1.92 (br m, 2H), 1.69 (AB, J=7.3 Hz, 2H).
Reaction SMILES: [Cl:1][CH:2](Cl)[CH3:3].[C:5]1([CH3:25])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[NH:13][CH:14]=[N:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24]>>[Cl-:1].[C:21]1([CH3:22])[CH:20]=[C:19]([CH3:23])[CH:18]=[C:17]([CH3:24])[C:16]=1[NH+:15]1[CH2:3][CH2:2][N:13]([C:6]2[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[CH3:25])[CH2:14]1
Reactant: CC(Cl)Cl
Reactant: Cc1cc(C)c(N=CNc2c(C)cc(C)cc2C)c(C)c1
Product: Cc1cc(C)c(N2CC[NH+](c3c(C)cc(C)cc3C)C2)c(C)c1
Product: [Cl-]
Temperature: 120 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
According to method B1, dichloroethane (1.36 mL) was added to a schlenk flask charged with N,N′-dimesitylformamidine (0.5 g, 1.78 mmol). The tube was evacuated until solvent began to bubble and then sealed and heated with stirring to 120° C. for 24 hours. The reaction mixture was then cooled, added to toluene (40 mL) and then brought to reflux. While still hot, the precipitate was collected by vacuum filtration, washed with toluene (5 mL) and dried in vacuo to afford 1,3-dimesitylimidazolinium chloride (0.3 g, 49%) as a light peach powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][C:14]([NH2:18])([C:16]#[CH:17])[CH3:15].[CH2:19]([NH2:21])C.CN>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9](=[O:11])(=[O:10])[NH:18][C:14]([CH3:15])([CH3:13])[C:16]=2[CH2:17][NH:21][CH3:19])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: CCN
Agent: CN
Product: CNCC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C

Procedure:
The title compound was prepared from (4-chlorophenyl)methanesulfonyl chloride and 1,1-dimethylpropargylamine according to the procedure described for Intermediate 4 replacing ethylamine by methylamine in the last step. 1H-NMR (DMSO-d6) δ 7.72 (bs, 1 H), 7.53 (m, 4H), 3.33 (s, 2 H), 2.16 (s, 3 H), 1.45 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CN1CCNCC1
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
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), 1-methylpiperazine (144 mg, 1.437 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 1.5 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to obtain a purified product (0.253 g) in 50.3% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][NH:21][CH2:20]4)[CH2:14][CH2:13]3)[C:9]2=[O:30])=[CH:5][CH:4]=1.[CH:33]1([CH2:36][CH2:37]C(O)=O)[CH2:35][CH2:34]1.CC(C)N=C=NC(C)C.CN(C=[O:54])C>CN(C1C=CN=CC=1)C>[CH:33]1([CH2:36][C:37]([N:21]2[CH2:22][C@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:19]([CH2:18][N:15]3[CH2:16][CH2:17][C:10]4([C:9](=[O:30])[N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=5)[CH2:12][CH2:11]4)[CH2:13][CH2:14]3)[CH2:20]2)=[O:54])[CH2:34][CH2:35]1
Reactant: O=C(O)CCC1CC1
Reactant: COc1ccc(CN2CCC3(CCN(C[C@H]4CNC[C@@H]4c4ccccc4)CC3)C2=O)cc1
Reactant: CN(C)C=O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Product: COc1ccc(CN2CCC3(CCN(C[C@H]4CN(C(=O)CC5CC5)C[C@@H]4c4ccccc4)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 100 mg (0.23 mmol) of 2-(4-methoxy-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one in DMF (1 mL) was added cyclopropylmethylacetic acid (39 mg, 0.311 mmol), DIC (31 μL, 0.311 mmol) and DMAP (8 mg, 0.065 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by flash silica chromatography eluting first with ethyl acetate:hexanes (20%-100%) and then with methanol:dichloromethane (1:25) to give 116 mg (72%) of 8-[(3S,4S)-1-(2-cyclopropyl-acetyl)-4-phenyl-pyrrolidin-3-ylmethyl]-2-(4-methoxy-benzyl)-2,8-diaza-spiro[4.5]decan-1-one. The compound was then dissolved in methanol (2 mL) and HCl (aq., 0.2M, 3 mL) and stirred for 10 minutes. The solvent was removed in vacuo, and the solution lyophilized to give the Compound 117 (120 mg, 95%).
Reaction SMILES: [CH:1]1([C:5]2[C:13](I)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>CCOCC>[CH:1]1([C:5]2[C:13]([CH:17]=[O:16])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Temperature: -78 °C
Yield: 41 %

Procedure:
Into a three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 5.00 g, 12.7 mmol, 1.00 equiv, 80%) in a solvent mixture of tetrahydrofuran and Et2O (50/50 mL). This was followed by the addition of butyllithium (15 mL, 2.50 equiv, 95%) dropwise with stirring at −78° C. To this was added N,N-dimethylformamide (2.50 g, 32.5 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at −78° C. and then carefully quenched by slow addition of 50 mL of NH4Cl (aq.). The pH was adjusted to 1-2 with hydrogen chloride (6 M). The resulting solution was diluted with 100 mL of ethyl acetate, then washed with 4×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as eluent to furnish 1.62 g (41%) of 4-cyclobutyl-5-formyl-2-methylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1CCO.N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:5]([O:4][CH2:2][CH2:1][CH:9]1[CH2:8][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCC1Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Ac2O (47 mL, 505 mmol) in DCM (50 mL) was added over 1 h to a stirred solution of alcohol 149 (54.5 g, 337 mmol), pyridine (52 mL, 981 mmol) and DMAP (1.65 g, 13 mol) in DCM (400 mL) and the resulting solution was stirred at 20° C. for 16 h. H2O (200 mL) was added, and the mixture stirred for 1 h. The organic fraction was washed with aqueous HCl solution (1 M, 100 mL) and H2O (150 mL), dried and the solvent evaporated to give acetate 150 (68.4 g, 99%) as a pale brown oil: 1H NMR δ 7.16-7.19 (m, 2H, Harom), 7.09-7.14 (m, 2H, Harom), 4.16 (t, J=6.8 Hz, 2H, CH2O), 3.04-3.10 (m, 2H, CH2), 2.48-2.66 (m, 3H, CH2, CH), 2.05 (s, 3H, COCH3), 1.85 (q, J=6.8 Hz, 2H, CH2); 13C NMR δ 171.1, 143.0 (2), 126.2 (2), 124.4 (2), 63.5, 39.1 (2), 37.0, 34.3, 21.0. Anal calcd for C13H16O2: C, 76.4; H, 7.9. Found: C, 76.6; H, 7.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Solvent: CN(C)C=O
Product: CC(C)CCn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 200 mg, 0.62 mmol) and 1-iodo-3-methylbutane (410 μL, 3.1 mmol) in dimethylformamide (4 mL) was heated at 100° C. overnight and then stirred at room temperature over the weekend. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 65% ethyl acetate/petroleum ether, and dried under high vacuum over the weekend to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1-(3-methyl-butyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (91 mg, 38%) as an off-white solid. APCI(+)-MS (M+H) 391.
Reaction SMILES: [O:1]([C:14]1[CH:19]=[CH:18][C:17](C(=O)CSC#N)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9]SC#N)=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.[Cl:39][CH2:40][C:41](Cl)=[O:42].[Cl-:44]>C(=S)=S>[O:1]([C:14]1[CH:19]=[CH:18][C:17]([C:41](=[O:42])[CH2:40][Cl:39])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][Cl:44])=[CH:4][CH:3]=1
Reactant: N#CSCC(=O)c1ccc(Oc2ccc(C(=O)CSC#N)cc2)cc1
Reactant: [Cl-]
Reactant: O=C(Cl)CCl
Solvent: S=C=S
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(CCl)c1ccc(Oc2ccc(C(=O)CCl)cc2)cc1

Procedure:
This invention concerns the compound oxybis(4,1-phenylene(2-oxo-2,1-ethanediyl)) thiocyanate, hereinafter referred to as "Compound", corresponding to the formula ##STR1## Compound is prepared by reacting diphenyl oxide with chloroacetyl chloride in the presence of alumnium chloride in carbon disulfide reaction medium, whereby 1,1'-(oxydi-4,1-phenylene)bis[2-chloroethanone] is formed. The latter is then reacted with alkali metal thiocyanate, advantageously potassium thiocyanate, in acetone as reaction medium to form Compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.C(N)[CH2:17][NH2:18].[CH3:20][N:21](C)C=O>>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:20]#[N:21])=[CH:9][CH:8]=3)#[N:18]
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CN(C)C=O
Reactant: NCCN
Product: N#Cc1ccc2[nH]c3ccc(C#N)cc3c2c1

Procedure:
A slurry of 3,6-dibromocarbazole (33.3 g) and cuprous cyanide (39 g) in 50 ml of dimethylformamide is heated at 160° C for seven days. The reaction mixture is poured into 1 liter of aqueous ethylenediamine (20%, v/v) and the mixture is stirred for fifteen minutes and filtered. The precipitate is slurried in 1 liter of aqueous ethylenediamine (20%, v/v) and stirred for about 16 hours. The precipitate is collected by filtration and recrystallized from dimethylformamide to yield 15 g of 3,6-dicyanocarbazole, melting point 360° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:21])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C.CC(OC)(C)C>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:9](=[O:21])[O:10][C:11]=2[CH:18]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Solvent: CCO
Solvent: COC(C)(C)C
Product: COc1ccc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 29 %

Procedure:
Process A; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 26) and 1-(2-methoxyphenyl)piperazine; yield 29%; m.p. 129°-130° C. (from ethanol/TBME).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1.Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].[CH3:47][C:48]1[CH:49]=[C:50]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[C:51](=[O:54])[NH:52][N:53]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:30])([F:31])[F:32])[CH2:28][CH2:27]3)=[CH:24][N:25]=[C:20]2[C@H:19]([NH:33][C:35]([N:58]2[CH2:59][CH2:60][CH:55]([C:50]3[C:51](=[O:54])[NH:52][N:53]=[C:48]([CH3:47])[CH:49]=3)[CH2:56][CH2:57]2)=[O:36])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2c(F)cccc2F)Cn2c(C3(C(F)(F)F)CC3)cnc21
Reactant: Cc1cc(C2CCNCC2)c(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4c(F)cccc4F)Cn4c(C5(C(F)(F)F)CC5)cnc43)CC2)c(=O)[nH]n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
Triethylamine (55 μL, 0.39 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,6-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (40 mg, 0.10 mmol) and 4-nitrophenyl chloroformate (22 mg, 0.11 mmol) in tetrahydrofuran (5 mL) at 0° C. After 30 min, 6-methyl-4-piperidin-4-ylpyridazin-3(2H)-one (38 mg, 0.20 mmol), triethylamine (55 μL, 0.39 mmol) and chloroform (5 mL) were added and the mixture was heated to 50° C. After 30 min, the reaction mixture was allowed to cool to ambient temperature. Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic extracts were washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (15 mg). MS 591.2536 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17][Li]>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([CH3:17])([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: [Li]C
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCCc2nc3ccccc3c(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of dry tetrahydrofuran was suspended 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one at ice temperature and 78 ml (4 eq) of 1.2M CH3Li solution in ether was added thereto at such a rate as to avoid bubbling. The reaction mixture was stirred overnight as it warmed to ambient temperature. The next day 20 ml more of the CH3Li solution was added to drive the reaction to a completion. After 0.5 hour the reaction was quenched with excess water and 4.97 g of the precipitate was collected and air dried. The product was recrystallized from MeOH/toluene. The yield was 2.06 g (38%) of granules, melting point 250° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[C:15]3[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][N:8]2[C:22](=[O:25])[C:23]=1[OH:24])=O.C[O-].[Na+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CO>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:3]([C:5]2[N:6]=[C:7]3[C:15]4[C:14]([N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][N:8]3[C:22](=[O:25])[C:23]=2[OH:24])=[O:2])=[CH:32][CH:31]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2c3c(N4CCOCC4)cccc3[nH]n2c(=O)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2c3c(N4CCOCC4)cccc3[nH]n2c(=O)c1O
Temperature: 25 °C
Yield: 38.4 %

Procedure:
The product from Example 21.2 (172 mg, 0.5 mmol), sodium methoxide (54 mg, 1.0 mmol) and 4-fluoro benzylamine (1.87 mg, 1.5 mmol) in methanol (15 mL) were combined and heated with stirring at reflux overnight. The mixture was cooled to room temperature and the resulting solid was collected by filtration and dissolved in dichloromethane (30 mL). The solution was washed with aqueous hydrochloric acid (2.0 M), water, dried and concentrated in vacuo to afford desired compound (84 mg, 38.4).
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH:1]1([NH:6][C:7]([NH:9][C:10]2[N:15]=[N:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCC1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CCCC1

Procedure:
Following the procedure of Example 5, making variations only as required to use cyclopentylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (91% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.02, 7.82, 7.75, 7.65, 7.58, 7.51, 7.34, 3.91-3.98, 3.67-3.80, 3.46-3.58, 3.36-3.44, 3.11-3.35, 1.80-1.88, 1.46-1.67, 1.30-1.40. MS (ES+) m/z 451 (M+1).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:39]=[CH:38][C:27]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:38][CH:39]=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: [H][H]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)OCc4ccccc4)cc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)O)cc3)CC2)C1
Yield: 97.4 %

Procedure:
In a round-bottom flask, a solution of benzyl 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoate (120 mg, 0.20 mmol) in methanol (400 μL) and Palladium (10%) on Carbon (50 mg) was purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas for two hours. The flask was purged with argon, then the mixture was filtered and concentrated to afford 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoic acid (101 mg, 96%) as an off-white solid. 1H-NMR (CD3OD) δ: 1.60-1.98 (m, 4H), 1.90-2.40 (m, 4H), 2.85-3.05 (m, 3H), 3.38-4.10 (m, 8H), 4.40-5.58 (m, 1H), 7.01 (d, J=9.0 Hz, 2H), 7.70 (t, J=8.1 Hz, 2H), 7.84-7.90 (m, 1H), 7.89 (d, J=8.7 Hz, 2H), 8.15 (d, J=7.8 Hz, 1H), 8.22 (s, 1H). MS m/z: 519 (M+1).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][CH:20]2[OH:23])=[CH:16][CH:15]=1.CCOCC>C(Cl)Cl>[F:12][C:13]([F:24])([F:25])[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][C:20]2=[O:23])=[CH:16][CH:15]=1
Reactant: OC1C=Cc2ccc(C(F)(F)F)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1C=Cc2ccc(C(F)(F)F)cc21
Reaction time: 14 h
Yield: 40.4 %

Procedure:
To a solution of pyridinium chlorochromate (1.08 g, 5.0 mmol) in methylene chloride (15 mL) was added dropwise a solution of 6-(trifluoromethyl)-1H-inden-1-ol (500 mg, 2.498 mmol) in methylene chloride (10 mL). After being stirred for 14 h, ether (30 mL) was added, and the reaction mixture was filtered through silica gel. The filtrate was concentrated in vacuo. The crude material was chromatographed (10:1 hexane/EtOAc) to afford 200 mg (40%) of the product. LC-MS [M+1]=199.2.