Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](OC)=[O:23])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(N2CC(COC3C=CC(CCC(OC)=O)=CC=3)OC2=O)=CC=1>>[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:18][CH:19]=3)[O:9][C:8]2=[O:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Agent: COC(=O)CCc1ccc(OCC2CN(c3ccc(Cl)cc3)C(=O)O2)cc1
Product: O=C1OC(COc2ccc(CCCO)cc2)CN1c1ccccc1
Yield: 48 %

Procedure:
The same procedure of Example 34 was repeated except that methyl 3-[4-(3-phenyl-2-oxooxazolidin-5-yl)methoxyphenyl]propionate (compound 189) obtained in Example 31 was used in lieu of methyl 3-{4-[3-(4-chlorophenyl)-2-oxooxazolidin-5-yl]methoxyphenyl}propionate to give the title compound (compound 195) in a yield of 48%.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](Cl)=[N:6][CH:5]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[OH-].[K+]>CS(C)=O.CN(C=O)C.C(O)(=O)C>[CH2:13]([NH:20][C:7]1[C:8]([Br:10])=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][N:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(NCc2ccccc2)c(Br)c1
Temperature: 160 °C
Yield: 50 %

Procedure:
A mixture of 0.3 g (1.27 mmol) 5-bromo-6-chloro-nicotinic acid methylester and 0.34 g (3.17 mmol) benzylamine in 0.4 mL DMSO was heated to 160° C. in the microwave for 4 min. 0.6 mL water and 0.4 mL 5N KOH aq was added and heated to 160° C. in the microwave for 2 min. Acetic acid and DMF was added and the mixture was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 0.195 g (50%) of the title compound. MS (m/e): 307.1 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][O:49][CH:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([CH2:63][NH:64][CH3:65])=[CH:59][CH:58]=2)[CH2:52][CH2:51]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:64]([CH2:63][C:60]3[CH:59]=[CH:58][C:57]([CH2:56][N:53]4[CH2:54][CH2:55][CH:50]([O:49][CH3:48])[CH2:51][CH2:52]4)=[CH:62][CH:61]=3)[CH3:65])=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.15 mmol), HOBt (23 mg, 0.17 mmol) DIPEA (0.04 mL, 0.22 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (39 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22](Cl)=[O:23]>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:23]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 88.1 %

Procedure:
To a solution of 4-fluoro-3-nitro-phenylamine (3.0 g, 20 mmol) in dichloromethane (60 mL) was added pyridine (3.2 g, 40.0 mmol). The solution was cooled to 0° C. and 3,5-dichlorobenzoyl chloride (4.0 g, 20.0 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room temperature over 18 h. The reaction was poured into water and a precipitate formed. The solid was collected and washed with excess water. This solid was than dried under vacuum at 50° C. for 18h. This solid was taken up in ethyl acetate. The ethyl acetate was washed with 5% HCl, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (5.8 g, 92%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH2:32][C@H:31]3[CH2:35][N:36](C(OC(C)(C)C)=O)[CH2:37][C@H:30]3[CH2:29]2)=[CH:24][CH:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[C:33](=[O:34])[CH2:32][C@H:31]6[CH2:35][NH:36][CH2:37][C@H:30]6[CH2:29]5)=[CH:26][N:27]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC(=O)N(c3ccc(N)nc3)C[C@@H]2C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CNC[C@@H]5CC4=O)cn3)nc2n1C1CCCC1
Yield: 86 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and cis-tert-butyl 5-(6-aminopyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate were combined and gave after purification cis-tert-butyl 5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (81 mg) in 86% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.79 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.24 (d, J=2.53 Hz, 1H), 7.63 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.46 (s, 1H), 4.81 (m, 1H), 3.84 (dd, J1=13.14 Hz, J2=5.56 Hz, 1H), 3.78-3.63 (m, 3H), 3.49-3.21 (m, 2H), 3.16 (s, 6H), 2.79 (m, 3H), 2.55 (m, 3H), 2.07 (m, 4H), 1.72 (m, 2H), 1.48 (s, 9H). LCMS m/z 589.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:32]([C:29]2[N:26]3[C:25]([S:24][CH:28]=[CH:27]3)=[N:31][CH:30]=2)=[O:33])=[O:8])[N:6]=1
Reactant: O=C(O)c1cnc2sccn12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=483.3.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cnc(Cl)c(F)c2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.74 min, UPLC-MS (Condition 3) tR=1.16 min, m/z=497.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 3H) 3.60 (s, 4H) 5.48 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.00-8.15 (m, 2H) 8.38 (d, J=1.95 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.C(OCC)C.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>C1COCC1>[C:11]([C:10]1[S:9][C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:16])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Compound 98 (354 mg, 0.989 mmol) was dissolved in THF (5 mL), and a diethyl ether solution of 3 mol/L phenylmagnesium bromide (1.32 mL, 3.96 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with ethanol to afford the entitled Compound 99 (220 mg, 59%) as pale yellow crystals.
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:8])[CH:6]=O)C.Cl.[OH:10][CH2:11][C:12]([NH2:14])=[NH:13]>>[OH:10][CH2:11][C:12]1[N:14]=[CH:4][C:5]([CH3:8])=[CH:6][N:13]=1
Reactant: CCOC=C(C)C=O
Reactant: N=C(N)CO
Agent: Cl
Product: Cc1cnc(CO)nc1

Procedure:
2-Hydroxymethyl-5-methylpyrimidine was prepared by the reaction of 3-ethoxy-2-methyl acrolein and hydroxyacetamidine hydrochloride following a similar procedure to that described by Kim and McKee (J. Org. Chem., 35, 455 (1970)). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.32 (3H,s); 3.6 (1H,bs); 4.80 (2H,s); 8.54 (2H,s).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[C:18]([Cl:20])[N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1.[CH3:21][NH:22][CH3:23]>C1COCC1>[Cl:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][N:22]([CH3:23])[CH3:21])=[CH:5][CH:6]=2)[N:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CCBr)cc2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nc(-c2ccc(CN(C)C)cc2)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(4-(bromoethyl)phenyl)-6-chloroisonicotinate (0.533 g, 1.56 mmol) in THF, dimethylamine (7.8 mL, 2M solution in THF) was added and reaction mass soared at rt for overnight. On completion, reaction mass concentrated and crude obtained was purified by column chromatography over silica gel obtaining pure methyl 2-chloro-6-(4-((dimethylamino)methyl)phenyl)isonicotinate (0.48 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]([F:29])([F:28])[C:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([C:22]2([C:21]([F:29])([F:28])[F:20])[CH2:24][CH2:23]2)=[O:26])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)C3(C(F)(F)F)CC3)ccc2F)NC(=S)CO1
Yield: 92 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (110 mg, 0.39 mmol) and commercially available 1-trifluoromethyl-cyclopropanecarboxylic acid [CAS No. 277756-46-4] (67 mg, 0.44 mmol). The compound was obtained as light yellow foam (167 mg, 92%). MS (ISP): m/z=419.2 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:29]#[C:30][CH3:31]>C1COCC1.[Cu]I>[Cl:27][C:23]1[N:24]=[CH:25][NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([C:29]#[C:30][CH3:31])[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:28])=[O:21]
Reactant: C#CC
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 44.8 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (70.0 mg, 0.145 mmol), Palladium dichlorobistriphenylphosphine(II) (7.55 mg, 0.014 mmol), copper(I)iodide (1.377 mg, 7.23 μmol) and TEA (0.101 ml, 0.723 mmol) in THF (4 ml) was bubbled 1-propyne (11.59 mg, 0.289 mmol) for 5 minutes and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-propyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (29 mg, 0.065 mmol, 45% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.60-7.81 (m, 1H), 7.40 (s, 1H), 7.28-7.38 (m, 3H), 7.16 (s, 1H), 7.05 (s, 1H), 4.62 (s, 2H), 1.99 (s, 3H). LC-MS (ES+) m/z 443.13, [M+H].
Reaction SMILES: [I:1]I.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:27]1([CH2:33][S:34]([CH2:37][CH2:38][CH2:39][CH2:40]O)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[I:1][CH2:40][CH2:39][CH2:38][CH2:37][S:34]([CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(CCCCO)Cc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(CCCCI)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of iodine (1.2 g, 4.5 mmol), imidazole (0.34 g, 4.4 mmol) and Ph3P (1.2 g, 4.4 mmol) in methylene chloride (10 mL) is added 4-phenylmethanesulfonylbutan-1-ol (0.99 g, 4.34 mmol) and the mixture is stirred at RT for 1 h. The mixture is filtered and the filtrate evaporated. The resulting oil is dissolved in EtOAc and washed with saturated sodium thiosulfate and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting solid is washed with ether and the filtrate is evaporated to give the title compound as a white solid.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]12[CH2:36][CH2:35][CH2:34][C:32]3[C:33]1=[C:28]([CH:29]=[CH:30][CH:31]=3)[NH:27][C:26]2=[O:37]>CN(C=O)C>[CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][CH2:23][CH2:24][C:25]12[CH2:36][CH2:35][CH2:34][C:32]4[C:33]1=[C:28]([CH:29]=[CH:30][CH:31]=4)[NH:27][C:26]2=[O:37])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2c([nH]c4ccccc24)C1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A 168 mg (0.98 mmol) portion of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 269 mg (1.96 mmol) of potassium carbonate were added to 3 ml of DMF solution containing 150 mg (0.49 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one and stirred overnight at room temperature. The reaction solution was extracted with chloroform and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the residue was recrystallized from acetone to obtain 98 mg of the title compound (48% in yield). An oily material obtained by concentrating the mother liquid was purified by a silica gel column chromatography (30 cc; elution by chloroform-methanol=15:1) to obtain 73 mg of the title compound (38% in yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:25][CH3:26])[C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Compound 13B (800 mg, 2.76 mmol) dissolved in DMF (10 ml) was added with K2CO3 (1.1 equiv., 420 mg) and ethyl iodide (1.1 equiv., 0.3 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 750 mg of 14B as a semisolid. Yield=85.5%. 1HNMR (DMSO, 200 MHz) δ 1.096 (3H, t, J=7.2 Hz), 1.17 (2H, m), 1.43 (2H, bs), 3.34 (2H, m), 3.43 (3H, s), 7.68 (2H, m), 7.79 (2H, m)
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.Cl.CCOC(C)=O>C(O)(=O)C.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:3](=[O:16])[CH2:4][C:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: COC(=O)CC(=O)CCc1ccc(F)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(CCc2ccc(F)cc2)=NN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(4-fluoro-phenyl)-3-oxo-pentanoic acid methyl ester (0.43 g) in acetic acid (5 mL) in a sealable tube was added 4-fluorophenylhydrazine.HCl (0.31 g). The reaction vessel was sealed and immersed into an oil bath at 100° C. for 18 hours. The reaction vessel was cooled to ambient temperature, opened and the contents were poured onto a mixture of EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and dried over sodium sulfate. Filtration and evaporation of the volatiles in vacuo afforded a crude crystalline material. The crude product was washed with ether to afford the desired 2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-2,4-dihydro-pyrazol-3-one (0.37 g) as a beige crystalline solid. MS (ESI+): 301.1 [M+H]+).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25]1(=[O:30])[CH2:29][CH2:28][CH:27]=[CH:26]1.CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:27]3[CH2:28][CH2:29][C:25](=[O:30])[CH:26]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: O=C1C=CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A solution of N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (600 mg, 1.506 mmol), 2-cyclopenten-1-one (0.609 mL, 7.53 mmol), n-methyldicyclohexylamine (0.959 mL, 4.52 mmol) and bis(tri-tert-butylphosphine)palladium (0) (77 mg, 0.151 mmol) in Dioxane (4 mL) was capped, degassed and backfilled with argon. The reaction was heated to 90° C. After 6 h, the reaction was heated to 110° C. After 36 h, the reaction was cooled to 23° C., diluted with EtOAc (150 mL) and washed with water (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-3% methanol/dichloromethane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 400.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]5[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].[H-].[Na+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][N:12]1[C:11]2[C:10]([CH3:16])([CH3:15])[C:9]3[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]4[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]4)[CH:19]=[CH:20][C:8]=3[C:7](=[O:39])[C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: COC(=O)CBr
Reactant: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H]3OC(C)(C)O[C@@H]3CO[Si](C)(C)C(C)(C)C)cc1C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Under nitrogen atmosphere, 3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T22-1, 40.0 mg, 65.2 μmol) was dissolved in DMF (0.20 mL), added at 0° C. with methyl bromoacetate (30.5 μL, 134.5 μmol) and sodium hydride (4.5 mg, 132 μmol), and then stirred at room temperature for 2 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (44.5 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:12]C(=O)C)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1>[OH-].[Na+].CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CC(=O)OC1CCCc2cc(C)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc2c(c1)CCCC2O
Temperature: 65 °C

Procedure:
4.11 Grams of 3-methyl-8-acetoxy-5,6,7,8-tetrahydroquinoline was dissolved in 15 ml of 30%-sodium hydroxide aqueous solution and 15 ml of methanol, the thus obtained mixture was stirred with heating at 65° C. for 3 hours. The solvent was removed by evaporation, and the residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to obtain 1.50 g of 3-methyl-8-hydroxy-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N:12]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl>[NH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[N:8][CH:7]=1)[NH2:12]
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a cold solution of 6-(trifluoromethyl)pyridin-3-amine (1.5 g, 9.25 mmol) in 4N HCl (60.0 mL) was added aqueous solution of NaNO2 (0.766 g, 11.11 mmol) at 0° C. The reaction mass was stirred at same temperature for 30 minutes. The reaction mass was added to a solution of SnCl2.H2O in 4N HCl at 80° C. and further continued stirring for 5-6 h at same temperature. The reaction mass was cooled, basified and extracted with DCM. The organic layer was dried and concentrated to afford 0.700 g of the product. 1H NMR (300 MHz, DMSO d6): δ 4.29 (br s, 2H), 7.18 (dd, J=8.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 8.13 (d, J=2.4 Hz, 1H); MS (m/z): 178.15 (M+H+).