Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.[OH:21][CH2:22][C:23]1([NH2:26])[CH2:25][CH2:24]1>>[OH:21][CH2:22][C:23]1([NH:26][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: NC1(CO)CC1
Reactant: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1C[C@H]1C[C@@H]21
Product: O=C(NC1(CO)CC1)c1nn(-c2ccc(Cl)cc2Cl)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(2,4-dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (1-hydroxymethyl-cyclopropyl)-amine. LCMS m/z=378.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.51 (td, J=4.6 and 3.4 Hz, 1H), 0.90-1.03 (m, 4H), 1.14-1.21 (m, 1H), 2.00-2.07 (m, 1H), 2.27-2.37 (m, 1H), 2.97 (d, J=16.6 Hz, 1H), 3.06 (dd, J=16.6 and 6.3 Hz, 1H), 3.71 (s, 2H), 7.28 (bs, 1H), 7.40 (dd, J=8.5 and 2.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:35])[F:36])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccccc1C(F)(F)F)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 85 °C
Yield: 21.8 %

Procedure:
The mixture of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.280 mmol), 1-[2-(trifluoromethyl)phenyl]methanamine (0.075 g, 0.430 mmol), 1,2,4-traizole (0.004 g, 0.05 mmol) and DBU (0.009 g, 0.005 mmol) was heated at 80-90° C. in seal tube for 15 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was washed with dilute HCl and water, dried over anhydrous sodium sulphate and concentrated to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.66-4.68 (d, J=4.2 Hz, 2H), 7.45-7.75 (m, 7H), 8.05 (s, 4H), 9.16 (br s, 1H), 12.73 (br s, 1H); MS (m/z): 489.42 (M−H)−.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][NH2:36])=[O:34])=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:36][CH2:35][C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])=[O:6])[CH3:3]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
BOC-Ala-OH (94.6 g.), H-Gly-OBzl.TosOH (168.8 g.) and HOBT (67.6 g.) were dissolved in THF (450 ml.) and WSC (91.5 ml.) was added thereto, then stirred for 1 hour at 0° C. and overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (800 ml.). 1 N HCl (500 ml.) was added, the precipitate was removed by filtration, and the ethyl acetate layer was washed with 1 N HCl (400 ml.), and twice with 5% sodium bicarbonate solution and water in this order, and, after drying with anhydrous magnesium sulfate, concentrated in vacuo. The residue was treated with n-hexane to obtain crude material (152.5 g.) Recrystallization was carried out twice by ethyl acetate - n-hexane to obtain BOC-Ala-Gly-OBzl (144 g., Yield: 85.7%, m.p.: 87° - 88.5° C., TLC: one spot, RF1 = 0.59).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH2:21](S(O)(=O)=O)C.CCCCCC>C(OCC)(OCC)OCC>[Cl:20][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[N:1]=[CH:21][N:8]2[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(CNc2ncnc(Cl)c2N)cc1OC
Reactant: CCS(=O)(=O)O
Solvent: CCCCCC
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Cn2cnc3c(Cl)ncnc32)cc1OC

Procedure:
To a suspension of 15.6 g (52.8 mmols) of 5-amino-4-chloro-6-(3,4-dimethoxybenzylamino)pyrimidine in 100 ml of triethyl orthoformate was added 149 mg (1.36 mmols) of ethanesulfonic acid and the resulting mixture was heated at 80° for 15 min. Upon cooling and addition of hexane to the reaction mixture, a yellow precipitate formed which was collected by filtration; yield, 15.4 g (95.6%) mp 159°-163°. Recrystallization from EtOH--H2O gave the analytical sample; yield 13.2 g (82.2%) mp 160°-164°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:11]=[C:10]([C:23]([OH:25])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[N:11]=[C:10]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C(F)(F)F)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3cccc(C(F)(F)F)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 82A in analogy to the synthesis of the compound of Example 1. 22 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]#[N:21])[CH2:3][CH2:2]1.C(=O)([O-])[O-:28].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]([NH2:21])=[O:28])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To an ice/water cooled suspension of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carbonitrile [P2] (6.0 g, 17.1 mmol) and potassium carbonate (7.09 g, 51.37 mmol) in DMSO (120 mL) was added hydrogen peroxide (25 mL, 35 wt. % in H2O) drop wise at a rate to ensure the temperature remained below 20° C. The mixture was stirred for 2 hours then diluted with DCM (800 mL). The solution was washed with water (3×500 mL) before the organic phase was dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave crude product that was purified by trituration with methanol giving (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carboxamide [P3] (4.50 g, 71% yield); LC/MS (r.t. 10.1 minutes [5 to 95% B]), 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](=[S:13])[N:12]=2)=[CH:4][CH:3]=1.[Na].Br[C:16]1[S:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([S:13][C:16]3[S:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: S=C1N=NC(c2ccc(Cl)cc2)=N1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [Na]
Product: O=[N+]([O-])c1cnc(Sc2nc(-c3ccc(Cl)cc3)n[nH]2)s1

Procedure:
The title compound was prepared in the manner described in Example 1. Substituting 4-chlorobenzoyl chloride for the benzoyl chloride in Example 1 gave 4-chlorobenzoyl thiosemicarbazide and then 3-(4-chlorophenyl)-1,2,4-triazole-5-thione. Reaction of 2.34 g of the sodium salt of 3-(4-chlorophenyl)l,2,4-triazole-5-thione with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1 yielded 1.5 g of 3-(4-chlorophenyl)-5-[(5-nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 181-184° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[S:20])[N:14]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]2=[O:27]>CN(C)C=O>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([S:20][CH3:1])[N:14]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]2=[O:27]
Reactant: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Br)cc2c(=O)n1CC1CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (6.0 g, 44 mmol), iodomethane (2.5 g, 1.1 mL, 17.6 mmol), and the title compound of Step A (3.0 g, 8.8 mmol) were combined in dimethylformamide (90 mL) and stirred for 2 h at room temperature. The reaction mixture was then concentrated to dryness under reduced pressure, and the ensuing residue was partitioned between 200 mL each of ethyl acetate and water. The phases were separated and the organic phase was subsequently washed with saturated aqueous NaCl and dried over Na2SO4 (anhydrous). Following solvent removal under reduced pressure and trituration of the resulting material with cold hexanes, 2.8 g of the title compound of Step B, a compound of the invention, was obtained as a solid melting at 68-72° C. 1H NMR (300 MHz, CDCl3):δ6 1.64-1.83 (m,1H), 1.80-2.18 (m,3H), 2.62 (s,3H), 3.78 (dd,1H), 3.96 (dd,1H), 4.17 (dd,1H), 4.21 (dd,1H), 4.38-4.50 (m,1H), 7.41 (d,1H), 7.73 (dd,1H), 8.36 (d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:38][CH2:37][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OCCc1ccccn1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCc5ccccn5)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-(2-pyridyl)ethanol. Yellow solid, 194 mg. ES-MS m/z 525 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[C:30](Br)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][CH:19]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[N:32]1([C:38](=[O:40])[CH3:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:30]2[C:25]([O:24][C:21]3[CH:22]=[CH:23][C:18]([N:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:19][CH:20]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:34][CH2:33]1)(=[O:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2s1
Reactant: CC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2cccnc2Oc2ccc(N(C(=O)OC(C)(C)C)c3nc4ccccc4s3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added tert-butyl benzo[d]thiazol-2-yl(4-(3-bromopyridin-2-yloxy)phenyl)carbamate (0.2713 g, 0.544 mmol), 1-(piperazin-1-yl)ethanone (0.140 g, 1.089 mmol), Pd2(dba)3 (0.050 g, 0.054 mmol), binap (0.068 g, 0.109 mmol), and cesium carbonate (0.174 mL, 2.177 mmol) in toluene to stir at 100° C. overnight. Reaction was allowed to cool to room temperature. Solvent was evaporated. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 10% to 100% over 15 min to provide tert-butyl 4-(3-(4-acetylpiperazin-1-yl)pyridin-2-yloxy)phenyl(benzo[d]thiazol-2-yl)carbamate (MS 545.6). It was taken up in DCM and TFA was added. After purification the title compound was obtained. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12](=[O:14])[N:11]([CH:15]([C:17]3[CH:27]=[CH:26][C:20]([C:21](OCC)=[O:22])=[CH:19][CH:18]=3)[CH3:16])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl.[Na+].[Cl-].CCN(C(C)C)C(C)C.Cl.[C:43]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])([CH3:46])([CH3:45])[CH3:44].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CO.O1CCOCC1.CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12](=[O:14])[N:11]([CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:51][CH2:50][CH2:49][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:52])=[O:22])=[CH:26][CH:27]=3)[CH3:16])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C(C)N2N=C(c3cc(Cl)cc(Cl)c3)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)N1N=C(c2cc(Cl)cc(Cl)c2)CC1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Ethyl 4-{1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoate (2.23 g, 5.50 mmol) was dissolved in MeOH-dioxane (1:1, 50 ml). A solution of NaOH (0.7 g/15 ml) was added. The mixture was heated to 60° C. for 1 hr. This was acidified with 2N HCl (10 ml), and the solvent was removed and residue vacuum dried to give a pale yellow solid (mixture of product acid and NaCl). This solid was suspended in DMF (15 ml), followed with DIEA (4.8 ml), beta-alanine t-butyl ester hydrochloride (3 g). A solution of PyBOP (3.43 g) in DMF (5 ml) was then added. After stirring at room temperature for 3 hr, more PyBOP (1 g) was added and the reaction mixture was stirred overnight. After addition of water (5 ml), the mixture was heated to 60° C. for 30 min. Ethyl acetate (150 ml) was added, and the organic layer was washed with 0.5 N HCl 2×, 5% K2CO3 2×, brine 2×. Evaporation of solvent gave an oily residue, which after flash column chromatography (SiO2, 0-30% ethyl acetate in DCM) afforded tert-butyl N-(4-{1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate as a white solid. NMR (500 MHz, DMSO-d6) δ: 1.37 (s, 9H); 1.78 (d, J=7.1 Hz, 3H); 2.45 (t, J=7.0 Hz, 2H); 3.42 (q, J=7.0 Hz, 2H); 5.56 (q, J=7.1 Hz, 1H); 5.99 (s, 1H); 7.30 (d, J=8.3 Hz, 2H); 7.47 (t, J=1.0 Hz, 1H). 7.73 (d, J=8.3 Hz, 2H); 7.76 (d, J=1.9 Hz, 2H); 8.43 (t, J=5.6 Hz, 1H); 11.34 (s, 1H). MS C25H27Cl2N3O4 Cald: 503.14; Obsd (M+Na): 526.05.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC([N:31]1[CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH2:33][CH2:32]1)=O)(C)(C)C>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:33]3[CH2:32][NH:31][CH2:36][CH2:35][CH:34]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCCNC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting materials 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine and 5-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. MS (ES+): m/z 422.05 (MH+, 35Cl, 37Cl), 424.06 (MH+, 37Cl, 37Cl).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=2)[CH2:9]1)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[N:19]1([CH2:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH:8]([NH2:7])[CH2:17][CH2:16]3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(CN3CCCCC3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C

Procedure:
(6-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (0.113 g, 0.327 mmol) was suspended in CH2Cl2 (2.5 mL) then TFA was added (2.5 mL). The reaction was stirred at RT until complete consumption of starting material was observed by HPLC analysis (2 h). The reaction mixture was concentrated in vacuo to afford the crude title compound as the bis-TFA salt, which was used without further purification. MS (APCI pos) 245 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH3:10])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].S(=O)(=O)(O)O.[CH3:16][OH:17]>>[CH3:16][O:17][C:2]([CH3:1])([CH2:9][CH3:10])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CCC(C)=CCCC(C)=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCC(C)(CCCC(C)=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2 kg 6-methyl-oct-5-en-2-one in 4 l methanol was added 800 ml concentrated sulphuric acid at 3° C. over a period of 40 minutes. After further stirring for 5 h at room temperature, the solution was poured onto 8 kg of ice water and extracted with tert.-butyl methyl ether. The combined organic phases were washed with 20% Na2CO3 (200 ml) and concentrated NaCl solution (3×150 ml). After removal of the solvent, the residue was distilled over a 70 cm Sulzer column to give 840 g recovered starting material (boiling point: 72°-75° C./10 mm Hg) and 970 g 6-methoxy-6-methyl-2-octanone (bp.: 95°-98° C./10 Torr=13.3 mbar).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: N#Cc1cccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>C(O)C>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A stirred solution of 5-cyanoindole (10.0 g, 70.3 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (15.4 g, 77.3 mmol), and pyrrolidine (14.7 mL, 175.7 mmol) in ethanol (200 mL) was heated at reflux for 20 hours then cooled to 0° C. The resulting precipitate was collected by vacuum filtration and rinsed with cold ethanol and hexanes to afford the product as a white solid (15.4 g, 68%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:24]CC2C=CC=CC=2)[C:14]=1[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[Si:17]([O:16][CH2:15][C:14]1[C:9]([OH:8])=[CH:10][N:11]=[CH:12][C:13]=1[OH:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(OCc2ccccc2)cncc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1c(O)cncc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3,5-bis(benzyloxy)-4-((tert-butyldimethylsilyloxy)methyl)pyridine (720 mg, 1.66 mmol, 1 eq.) in a mixture of EtOAc/EtOH (5/2, 28 mL) was added Pd/C (400.0 mg). The mixture was charged with H2 (60 psi), stirred at rt for 2 h, filtered, and concentrated to give 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 2H), 4.91 (s, 2H), 0.73 (s, 9H), −0.00 (s, 6H). LRMS (M+H) m/z 256.1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=C(N(C)C)C=1.C(OC(=O)C)(=O)C.Cl>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]2[C:18]4[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:20](=[O:21])[O:22]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Agent: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2c(-c3ccccc3)[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4.82 g (0.014 mole) of the 2-[(2-phenyl3-indolyl)carbonyl]benzoic acid from part A above, 3.60 g (0.02 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine, and five ml of acetic anhydride was slowly heated until a purple color formed and maintained at this temperature for approximately two hours. After cooling to room temperature, sufficient 3N hydrochloric acid was added to the mixture to effect solution and stirring was continued for approximately 1.5 hours The resulting solution was filtered and the pH adjusted to five by the addition of sodium acetate. The precipitate which separated from the solution was collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl[-3-(2-phenyl-3-indolyl)phthalide (Formula III: R°=R1 =R2 =R3 =R6 =Y1 =H; R=CH3 ; R4 =N(CH3)2 ; R5 =C6H5 9. After recrystalization from toluene and hexane, the off white-colored solid melted at 153°-155° C. Significant infrared maxima were observed at 3380 cm-1 (NH; m) and 1750 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the structure. A toluene solution of this product spotted on silica gel developed an intense grape-red-colored image.