Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: Cn1cccc(CBr)c1=O
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
3-Bromo-4-nitro-1H-indazole (Preparation B; 0.49 g, 2.04 mmol) was dissolved in dimethyl formamide (5 mL). Potassium carbonate (1.13 g, 8.15 mmol) was added followed by 3-(bromomethyl)-1-methylpyridin-2(1H)-one (0.41 g, 2.04 mmol). The mixture was stirred at ambient temperature for two days. The mixture was diluted with ethyl acetate (8 mL) and concentrated under vacuum to give a dark solid which was dried overnight under high vacuum. This material was dissolved in ethyl acetate (80 mL) and washed with water (40 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum to give a green solid. This material was triturated with diethyl ether and the solids were collected by filtration and dried under high vacuum to give 3-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one as a beige solid (552 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O-:12])=O.ClCl.S(Cl)([Cl:17])=O.P(Cl)(Cl)(Cl)=O.C(Cl)(=O)C(Cl)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:17])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])c1cc2ccccc2[nH]1
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1cc2ccccc2[nH]1

Procedure:
In step 1 of Scheme A, bromobenzaldehyde compound a is reacted with azido ester b under basic conditions to yield indole 2-carboxylate ester c. Compound c is then treated in step 2 with benzyl compound d in the presence of alkali metal hydride to afford 1-benzyl indole compound e. In step 3 a Buchwald reaction is carried out by reaction of compound e with protected piperazine f (other cyclic amine may be used) in the presence of suitable catalyst to provide piperazinyl indole g. The ester portion of compound g is hydrolized under basic conditions in step 4 to afford indole-2-carboxylate compound h. In step 5, indole-2-carboxylate compound h is reacted with a chlorine agent such as thionyl chloride, phosphorus oxychloride of oxalyl chloride, to afford indole-2-carboxylic acid chloride compound i. In step 6 acid chloride compound i is reacted with amine i to afford indole-2-carboxamide compound k. Compound k is then deprotected in step 7 to afford compound m, which is a compound of formula I in accordance with the invention.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:21]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1-c1ccccc1)c1ccccc1
Yield: 93.7 %

Procedure:
A 250 mL round bottom flask equipped with efficient magnetic stirring was charged with o-phenylphenol (17.0 g, 0.1 mol), toluene (100 mL) and triethylamine (11.1 g, 0.11 mol, 10% excess). Benzoyl chloride (14.7 g, 0.105 mol, 5% excess) was added portionwise over 15 minutes while using an ice bath to help maintain the temperature below 30° C. The initially clear reaction mixture became a white slurry during the acid chloride addition. After stirring at room temperature for an additional 2.5 hours, the slurry was filtered and the clear organic layer was stripped on a rotary evaporator at 60° C./P=3.4 kPa. The light yellow oil crystallized upon cooling. The crude product was recrystallized from a mixture of hexane (100 mL)/toluene (20 mL) yielding 25.7 g (93.8%) white crystals. The structure was confined using 13C and 1H NMR, IR and GC/MS.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][O-:14])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:29]1([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:10]=[CH:9]1
Reactant: CC1CCCCC1
Reactant: [O-]Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(COCC2CCCCC2)c[nH]1

Procedure:
5 mmol of sodium (1-triphenylmethyl-1H-imidazol-4-yl)-methanolate and 5 mmol of cyclohexylmethane chloride are treated as described in Example 5.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccc(Cl)c5)nc34)cc21
Temperature: 85 °C
Reaction time: 17 h
Yield: 19.1 %

Procedure:
Prepared according to Example 103, NaH as a 60% dispersion in mineral oil (143 μl, 3.29 mmol, Sigma Aldrich), 3-chlorophenol (334 μl, 3.29 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 140 mg, 0.470 mmol) and stirring at 85° C. for 17 h. Purification by column chromatography (silica gel, 0 to 60% EtOAc/DCM then 5% MeOH/DCM) providing 2-(2-(3-chlorophenoxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (35 mg, 19%). 1H NMR (400 MHz, CDCl3) δ ppm 11.28-11.38 (1H, m) 8.23 (1H, d, J=1.00 Hz) 8.04-8.09 (1H, m) 7.61-7.66 (1H, m) 7.48 (2H, q, J=1.00 Hz) 7.36-7.41 (2H, m) 7.19-7.26 (3H, m) 5.84-6.01 (1H, m) 3.58 (2H, t, J=1.00 Hz) 2.55 (2H, t, J=1.00 Hz). m/z (ESI, +ve) 390.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:13][C:12]([F:14])([F:15])[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: -80 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
3-Methoxy-5-nitrobenzotrifluoride (5 g, 23 mmol) was dissolved in anhydrous methylene chloride (100 mL) and cooled to −80° C. under a nitrogen atmosphere. To this solution was added via dropping fimnel a 1 M solution of BBr3 in methylene chloride (68 mL, 68 mmol). This solution was allowed to warm to room temperature and stirred for 3 days. Water was slowly added to the mixture and mixed well to quench the excess BBr3. To this mixture ether (500 mL) was added. The organic layer was separated and extracted with 2 N NaOH (240 mL). The alkaline extract was neutralized with dilute HC1 and extracted with diethyl ether (3×300 mL). The ether extracts were combined, washed with saturated NaCl and dried over anhydrous MgSO4. Evaporation of diethyl ether gave a brownish yellow oil which was chromatographed on a silica column to give 1.6 g (34%) of a yellow solid. 1H-NMR (CDCl3/CD3OD; 300 MHz) δ7.38-7.40 (m, 1 H), 7.82 (t, 1 H, J=2.2 Hz), and 7.95-7.96 (m, 1 H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:13][Li].Cl>C(OCC)C>[C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)(=[O:12])[CH3:13]
Reactant: [Li]C
Reactant: O=C(O)c1cccc2c1OCC2
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled suspension of 2,3-dihydrobenzofuran-7-carboxylic acid (D1) (2 g) in dry diethyl ether (100 ml) was added dropwise under argon, methyllithium (16.2 ml of a 1.5M solution in diethyl ether). The mixture was stirred at room temperature for 18 h, added to 5N hydrochloric acid (50 ml) and extracted into ethyl acetate. The organic phase was washed with potassium carbonate, then water and dried (Na2SO4). The solvent was evaporated under reduced pressure to leave the title compound as a plate lemon solid (1.5 g, 76%)
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:6]=1[NH:7]2.[CH2:19](Br)[CH:20]=[CH2:21]>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1C=CC=CC=1>[CH2:21]([N:7]1[C:8]2[C:4](=[CH:3][CH:11]=[CH:10][CH:9]=2)[C:5]2[C:18]3[C:13]([CH2:12][C:6]1=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:20]=[CH2:19]
Reactant: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Reactant: C=CCBr
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCn1c2c(c3ccccc31)-c1ccccc1C2
Reaction time: 12 h
Yield: 26.2 %

Procedure:
In a 0.5 l bulb were placed 100 ml 50% aqueous NaOH, 100 ml benzene, 6.1 g (28 mmol)of 5,6-dihydroindeno[2,1-b]indole, prepared in Example 4, 5 g (41 mmol) of allyl-bromide and 0.5 g of trimethylcetylammonium bromide. After having stirred the obtained mixture for 12 hours, the formation of an organic phase was observed; said phase was separated, washed twice with water (100 ml) and dried over Na2SO4. After removal of the solvent, the residue was passed through a column of silicagel, eluted with hexane/ethylacetate=5:1); the resulting solution was evaporated, obtaining 1.8 g of N-allyl-5,6-dihydroindeno[2,1-b]indole (yield=37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
To a solution of (2R, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35](O)=[O:36])=[CH:31][CH:30]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])[CH:34]=[CH:33][C:32]1[CH:38]=[CH:39][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 65 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 4-methoxycinnamic acid under the conditions described in example 86 to yield 65% of the desired product.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)=[C:28]=[O:29]>ClCCl>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:27][C:28]([N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:14][CH2:13]3)[CH2:16]2)=[O:29])=[CH:32][CH:33]=1
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Reactant: Cc1ccc(CN=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CNC(=O)N2CCC(N3CCC(c4ccccc4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (preparation #7) (0.050 g, 0.165 mmol) and triethylamine (0.092 mL, 0.66 mmol) in dichloromethane (1 mL) was added 1-isocyanatomethyl-4-methyl-benzene (0.024 g, 0.165 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 5% MeOH/EtOAc as the mobile phase to give 3-(4-phenyl-piperidin-1-yl)-pyrrolidine-1-carboxylic acid 4-methyl-benzylamide (0.042 g, 68%). RP-HPLC (Table 1, Method b) Rt 1.72 min; m/z: (M+H)+ 378.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)ccc1F
Yield: 37.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-fluoro-5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (145 mg, 0.230 mmol) was hydrolyzed by lithium hydroxide (48 mg, 1.15 mmol) in THF/methanol/water (15/5/5 ml) to yield 41 mg (37.6% yield) of the titled compound after purification by preparative TLC(Silicagel-1000 micron) using 50% ethyl acetate in hexane as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.44-8.40 (d, 1H), 8.108-8.101 (d, 1H), 7.83-7.74 (m, 2H), 7.58-7.50 (m, 2H), 7.40-7.10 (m, 5H), 4.46-4.42 (t, 2H), 3.20-3.16 (t, 2H), 3.06 (s, 3H). MS: m/z=476.5 (M+1), HPLC: 93.52% in method A.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[O:12]=[C:13]1[CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16][CH2:15][NH:14]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:12]=[C:13]1[CH:18]([C:19]([O:8][C@H:6]2[CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:20])[CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Reactant: CCOC(=O)C1CCCNC1=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)C1CCCNC1=O
Temperature: 25 °C

Procedure:
4-Dimethylaminopyridine (0.35 wt), (+)-menthol (0.95 wt) and ethyl 2-oxo-3-piperidinecarboxylate (1 wt) are dissolved/suspended in toluene (10 vol). The mixture is heated to reflux and stirred for seven days with periodic distillation of solvent and replenishment with fresh toluene. The reaction mixture is cooled to 25° C. and washed with two portions of 5% w/w aqueous HCl (4 vol) and then water (4 vol). The organic phase is concentrated under reduced pressure to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][CH3:16])=[C:12]([CH:14]=2)N)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:21]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][CH3:16])=[C:12]([Br:21])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 85 ml) is added dropwise to a suspension of 5-(4-chlorophenyl)-2-ethylaniline (14.3 g, 0.062 mol) in water (57 ml), and the mixture stirred. The mixture is cooled to −5° C. and a solution of sodium nitrite (5.07 g, 0.072 mol) in water (25 ml) is added dropwise, maintaining the temperature at 0-5° C. The reaction mixture is stirred for 1 hour, then added to a pre-cooled solution of cuprous bromide (9 g, 0.062 mol) in hydrobromic acid (48% wt. in water, 64 ml) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature overnight. The mixture is diluted with water, extracted with diethyl ether, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 2% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-ethyl-1-bromobenzene (10 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:39])[C:21]([C:23]1[N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28](Cl)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]>>[CH3:19][N:20]([CH3:39])[C:21]([C:23]1[N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]5[C:9]4=[O:18])=[CH:6][N:7]=3)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Reactant: Nc1ccc(N2CCN3CCCCC3C2=O)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCCC5C4=O)cn3)nc2n1C1CCCCC1
Yield: 16 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g, 0.244 mmol) was combined with 2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.075 g, 0.244 mmol, 1.0 eq) which gave 7-Cyclohexyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.020 g, 0.039 mmol) in 16% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.19-1.41 (m, 6H) 1.41-1.52 (m, 5H) 1.61-1.75 (m, 4H) 1.93 (br. s., 9H) 2.21 (td, J=11.37, 3.54 Hz, 2H) 2.40 (br. s., 2H) 2.52-2.81 (m, 7H) 2.93-3.05 (m, 4H) 3.16 (s, 11H) 3.47 (dd, J=11.37, 2.78 Hz, 2H) 3.93-4.09 (m, 2H) 4.26-4.42 (m, 2H) 6.44 (s, 2H) 7.68 (dd, J=8.84, 2.78 Hz, 2H) 8.00 (s, 2H) 8.23 (d, J=2.02 Hz, 2H) 8.63 (d, J=9.09 Hz, 2H) 8.71 (s, 2H) HRMS calc for m/z=517.3039. Found m/z=517.3046 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:41])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH:24]([CH3:40])[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:27]=3)=[CH:15][CH:14]=2)[N:7]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH:24]([O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)[N:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:9]=3)=[O:41])=[CH:14][CH:15]=2)[CH3:40])[CH:31]=[CH:30][N:29]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC(C)Cc3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC(C)Cc3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
To a stirred solution of the tert-butyl carbamate (50) (158 mg, 0.244 mmol) in DCM (4 mL) at 0° C. under nitrogen was added TFA (2 mL). After 5 min the reaction mixture was warmed to RT and stirred for a further 2 hr. The mixture was evaporated in vacuo and the residue was subjected to SCX capture and release to afford the title compound (Intermediate J) (138 mg, >100%): m/z 549 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1.S(=O)(=O)(O)O>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCCl)cc1
Agent: [Mn+4]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
4-(2-Chloroethyl)benzoic acid (2.00 g, 10.83 mmol) was dissolved in THF (40 ml) under an argon atmosphere, and 1M borane-THF complex (16 ml, 16.00 mmol) was slowly added dropwise under ice-cooling. After stirring at room temperature for 2 hours, 1N sulfuric acid (36 ml) was added, and the mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was dissolved in dichloromethane (50 ml). Manganese dioxide (10.00 g) was added, and the mixture was stirred overnight at room temperature. After filtration through celite, the filtrate was concentrated under reduced pressure to give the title compound (1.71 g, 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>>[F:29][C:11]([F:10])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([O:27][C:2]4[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)ccn1
Yield: 62 %

Procedure:
Obtained in 62% yield by an analogous procedure to Example 448, starting from 4-chloro-2-cyanopyridine and 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:16])[CH:3]=1.C[Al](C)C.N#N.[NH:23](/[C:27](/[CH3:33])=[CH:28]\[C:29](OC)=[O:30])[C:24]([CH3:26])=O>C(Cl)Cl>[O:15]=[S:11]1(=[O:14])[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[C:29](=[O:30])[CH:28]=[C:27]([CH3:33])[N:23]=[C:24]3[CH3:26])=[CH:3][C:4]=2[F:16])[CH2:9][CH2:10]1
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCS(=O)(=O)CC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenyl)1,1-dioxidothiomorpholine (1.20 g, 4.91 mmol) in anhydrous CH2Cl2 (100 mL) was added trimethylaluminium (28.5 mL, 28.5 mmol, 1 M in heptane) carefully dropwise under N2. Upon the end of addition the mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (2.32 g, 14.76 mmol) in anhydrous CH2Cl2 (30 mL). Upon the end of addition the reaction mixture was stirred at rt for another 15 h, then quenched with an appropriate amount of water and extracted with CH2Cl2. The combined organic phases were washed with brine, dried and concentrated in vacuo to give the title compound as a yellow solid (0.81 g, 47%). The compound was characterized by the following spectroscopic data: