Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu]C#N.[Cl-].[Li+].[CH2:6]([Zn]CC)[CH3:7].[F:11][C:12]1[C:13](/[C:22](/I)=[CH:23]/[C:24](=O)[C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15]2>C1COCC1>[CH2:6]([C:22]1[CH:23]=[C:24]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:15]2[C:16](=[O:21])[NH:17][C:18]3[C:14]=2[C:13]=1[C:12]([F:11])=[CH:20][CH:19]=3)[CH3:7]
Reactant: CC[Zn]CC
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) cyanide (Aldrich, 27 mg, 0.3 mmol) and lithium chloride (Fluka, 25.5 mg, 0.6 mmol) in dry THF (2 mL) was added diethylzinc (Aldrich, 1.0 M solution in n-hexane, 3.0 mL, 3.0 mmol), under argon, at −20° C. and the reaction mixture was stirred for 30 minutes at the same temperature. The light green reaction mixture was then cooled to −78° C. and treated dropwise with a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (79.2 mg, 0.2 mmol) in dry THF (4 mL). After stirring at the same temperature for 1 hour, the reaction mixture was allowed to warm up slowly to room temperature overnight, then heated under reflux for 3 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product which was further purified by preparative TLC (silica gel, 20% ethyl acetate in hexanes) to afford 5-ethyl-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 10.6 mg, 18.9%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[N:9]=1)=[O:7])(C)(C)C.C(OC1C(C(O)=O)=NC(CC2C=CC=C(Cl)C=2Cl)=NC=1O)C1C=CC=CC=1>>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Yield: 62.4 %

Procedure:
5-Benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (149) (16.5 g, 68%) as a brown solid was synthesized from 5-benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (148) (30 g, 63.69 mmol) following the procedure as described for 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (131).
Reaction SMILES: [Na].CC(C1C=CC=CC=1)=C.C1C=CC=CC=1.C1(C([Li])(C2C=CC=CC=2)CCCCC)C=CC=CC=1.[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][C:49]([C:51]([CH3:53])=[CH2:52])=[O:50].Cl.C[OH:56]>O1CCCC1>[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][C:49]([C:51]([CH3:53])=[CH2:52])=[O:50].[CH3:53][C:51]([C:49]([O:48][CH2:47][CH2:46][OH:56])=[O:50])=[CH2:52]
Reactant: CO
Agent: C=C(C)C(=O)OCCCCCCCCCCCC
Agent: C=C(C)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=C(C)C(=O)OCCO
Temperature: -78 °C

Procedure:
Under a high vacuum, a tetarahydrofuran solution of sodium salt of a-methylstyrene tetramer was introduced into a polymerization vessel, and removed after sufficiently washing the vessel. Then, 198 ml of tetrahydrofuran and 18 ml (3.0 mmole) of a benzene solution of 1,1-diphenylhexyl lithium were introduced under the room temperature into the vessel, which in turn was cooled to -78° C. Then, 111 ml (74 mmole) of a tetrahydrofuran solution of n-lauryl methacrylate was introduced into the vessel to start polymerization. After a lapse of 2 hours, the mixture was further stirred for 30 minutes with introduction of 95 ml (66 mmole) of a tetrahydrofuran solution of 3-methacryloylethoxydimethylisopropylsilane, thereafter the reaction was stopped with addition of 2 ml of methanol, and 1 ml of 2N-hydrochloric acid was added into the reaction vessel to obtain a block polymer of poly n-lauryl methacrylate and polyhydroxyethyl methacrylate. After the reaction was finished, the solvent was removed so that the nonvolatile content was 50%. Hydrophobic and hydrophilic blocks forming this block polymer exhibited molecular weights of 2410 and 1210 respectively.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl-].[NH4+]>CCO.O.[Fe]>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=1[Cl:20])[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(N)ccc1Cl
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a solution of 2-(2-chloro-5-nitro-phenyl)-malonic acid diethyl ester (2.3 g, 7.28 mmol) in EtOH (20 ml) and water (20 ml) was added Fe powder (2.0 g, 36.4 mmol) and ammonium chloride (2.0 g, 37.8 mmol). The mixture was heated at 100° C. for two hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between water and dichloromethane, and the organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 8:2) gave 1.35 g (65%) of 2-(5-amino-2-chloro-phenyl)-malonic acid diethyl ester as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][C:12]1[C:13]([C:22]2[C:23]3[CH:32]=[CH:31][O:30][C:24]=3[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)=[N:14][C:15](S(C)(=O)=O)=[N:16][CH:17]=1>CN(C=O)C>[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][C:12]1[C:13]([C:22]2[C:23]3[CH:32]=[CH:31][O:30][C:24]=3[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)=[N:14][C:15]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:16][CH:17]=1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccoc2c1=O
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccoc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A solution of methanesulfonamide (61 mg, 0.65 mmol) in DMF (2 mL) stirred at 0° C. under an atmosphere of nitrogen was treated with NaH (99 mg, 0.7 mmol). After the ice bath was removed, the mixture was stirred at rt for 15 min. The resulting suspension was treated with a solution of 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one (70 mg, 0.16 mmol) in DMF (1 mL). After the nitrogen inlet was removed, the capped mixture was heated to 70° C. for 3 h. After cooling to 0° C., the reaction mixture was stirred vigorously and treated water (500 uL). After 5 min, the cooled mixture was treated with 1N HCl(aq) (1 mL). The resulting suspension was filtered; the filter cake was washed with additional 1N HCl(aq) (1 mL) and isopropyl ether (5 mL) to afford the title compound (50 mg, 70%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.34 (s, 3H) 3.60 (s, 3H) 7.06 (m, 1H) 7.28 (m, 1H) 7.49 (m, 1H) 7.80 (s, 1H) 8.23 (s, 1H) 8.43 (m, 2H) 11.50 (bs, 1H). LCMS (M+H)+=449.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:26]([OH:27])=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]=[O:36].C(NC(C)C)(C)C>ClCCl>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[C:26]([OH:27])=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)([CH2:35][OH:36])[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=O
Reactant: Cc1ccc2c(c1)C(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one (1.61 g, 3.60 mmol) and para-formaldehyde (0.43 g, 14.6 mmol) in dichloromethane (60.0 mL) was added diisopropylamine (7.20 mmol). After stirring at ambient temperature for 3 h, the reaction was quenched with saturated aqueous ammonium chloride (60.0 mL). The organic layer was separated and washed with water (3×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (20-60%) to afford the title compound (1.07 g, 63%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 10.09 (br, 1H), 7.37-7.16 (m, 12H), 6.99 (s, 1H), 6.87 (d, 1H), 6.62 (s, 1H) 6.54 (s, 1H), 6.37 (d, 1H), 5.87 (d, 2H), 4.45 (ABq, 2H), 2.33 (s, 3H); MS (ES+) m/z 480.4 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@H:11]3[O:26][C:25](=[O:27])[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[C:21](=[O:30])[C@H:20]([CH3:31])[C@@H:19]([OH:32])[C@@H:18]([CH3:33])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]3)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:34].[OH:35]CC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CC#N.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@H:11]3[O:26][C:25](=[O:27])[CH2:24][CH2:23][C:22]([CH3:28])([CH3:29])[C:21](=[O:30])[C@H:20]([CH3:31])[C@@H:19]([OH:32])[C@@H:18]([CH3:33])[CH2:17][CH2:16][CH2:15][C@H:14]4[C@@H:13]([O:35]4)[CH2:12]3)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:34]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1nc2cc([C@@H]3CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)CCC(=O)O3)ccc2n1C
Agent: Cc1nc2cc([C@@H]3C/C=C/CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)CCC(=O)O3)ccc2n1C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1nc2cc([C@@H]3C[C@@H]4O[C@H]4CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)CCC(=O)O3)ccc2n1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 37 (30 mg, 0.064 mmol) in 1 mL CH3CN/DMM—1/1 at rt were added successively 0.6 mL of a buffer solution (Na2B4O7.10 H2O [0.05M] in Na2EDTA [4.10−4M]), Bu4N(HSO4) (0.9 mg, 0.0025 mmol) and fructose-derived ketone (13.2 mg, 0.051 mmol). The reaction mixture is cooled to 0° C. and were added separately, in a same time over 1 h30, Oxone® (55.1 mg, 0.089 mmol) in 0.8 mL Na2EDTA and K2CO3 (51.3 mg, 0.371 mmol) in 0.8 mL H2O. The solution is stirred at 0° C. for 3 h and then is quenched with H2O, extracted 3 times with 10 mL AcOEt. The combined organic layers are dried (MgSO4) and concentrated in vacuum. Purification by flash column chromatography (Hexane/Acetone/MeOH—70/30/0 to 45/50/5) afforded 38, 76% conversion.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: NC(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 47 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 47% of theory; LC (method 2): tR=3.35 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[N+:28]([C:31]1[NH:32][CH:33]=[C:34]([CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:35]=1)([O-])=O.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[N:37]1([CH2:36][C:34]2[N:35]=[C:31]([NH:28][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])[NH:32][CH:33]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: O=[N+]([O-])c1nc(CN2CCOCC2)c[nH]1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCOCC4)c[nH]3)c3nccnc23)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 2 h at 70° C. and using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1). 4-(2-Nitro-1H-imidazol-4-ylmethyl)-morpholine (Step 23.1) was used instead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 511.1 [M+H]+; tR=3.21 min (System 1); TLC: Rf=0.34 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1.[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25](O)[CH:24]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:29]([C:28]1[CH:23]=[CH:24][C:25]([O:19][C:18](=[O:20])[CH2:17][C:15]2[C:14]([C:21]#[N:22])=[CH:13][CH:12]=[C:11]([Cl:10])[N:16]=2)=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: N#Cc1ccc(Cl)nc1CC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylcarbodiimide (3.00 mL, 19.2 mmol) was added dropwise over 2 min at 0° C. with stirring to a homogeneous dark amber solution of crude (6-chloro-3-cyano-pyridin-2-yl)-acetic acid (3.1 g, 16 mmol; mixture of regioisomers), as prepared in the previous step, p-nitrophenol (3.35 g, 24 mmol), DMAP (11 mg, 0.8 mmol) and DCM (20 mL). The ice bath was removed immediately following the completion of DIC addition, and the dark amber solution was stirred at rt overnight. The crude reaction was allowed to stand at rt for some time, and was then loaded directly onto a silica flash column (90 mm×6″). Elution with 97:3 toluene/acetone afforded the impure title compound, but as a single regioisomer (566 mg, 14% from 2,6-dichloro-nicotinonitrile).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]I)(=[O:3])[CH3:2].C(COC)OC.CC([C@H]1N=C(C2C=CC=C(C3OC[C@@H](C(C)C)N=3)N=2)OC1)C.CC([C@@H]1N=C(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)OC1)C.[I:73][C:74]1[CH:81]=[CH:80][C:77]([CH2:78]Br)=[CH:76][CH:75]=1>CC(N(C)C)=O.Cl[Ni]Cl.CC([C@@H]1N=C(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)OC1)C.[Zn].Cl[Ni]Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:78][C:77]1[CH:80]=[CH:81][C:74]([I:73])=[CH:75][CH:76]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccc(I)cc1
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCI
Agent: Cl[Ni]Cl
Agent: CC(C)[C@@H]1COC(c2cccc(C3=N[C@H](C(C)C)CO3)n2)=N1
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Solvent: CC(=O)N(C)C
Solvent: COCCOC
Product: CC(=O)OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
Zinc powder (340 mg, 5.21 mmol) was dried in a 25-ml flask under high vacuum at 70° C. for 30 min, then DMA (1 ml) and 12 (44 mg, 0.17 mmol) were added. After 10 min, solution or 17-acetoxy-heptadecyl iodide (1.473 g, 3.47 mmol) in DMA (5 ml) was added. Reaction mixture was stirred at 60-70° C. for 10 h, cooled to room temperature and solution of the organozinc reagent was transferred via cannula into 25 ml round bottom flask equipped with the stir bar. The flask with organozinc solution 41 was immersed into an ice bath. In a 10-ml round bottom flask, NiCl2.glyme (76 mg, 0.347 mmol) and (R)-(i-Pr)-Pybox (or (S)-(i-Pr)-Pybox) (136 mg, 0.45 mmol) were dissolved in DMA (2 ml), then solution of p-iodobenzyl bromide (1.55 g, 5.21 mmol) in DMA (3 ml) was added. The solution of NiCl2-Pybox catalyst and p-iodobenzyl bromide was added to the solution of organozinc reagent 41 at 0° C. within 2-3 min. Reaction mixture was stirred at 0° C. for 30 min and at room temperature for 12-24 h. The reaction was quenched by addition of aqueous NH4Cl, extracted with EtOAc, extract was dried over Na2SO4 and evaporated. The crude product was purified by silica gel chromatography in hexane-ether (98:2) to give the product (1.58 g, 88%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:15]([CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCCCC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC1CNCCC1O

Procedure:
A mixture of 1-benzyl-3-n-butyl-4-hydroxypiperidine (2.5 g, 10.0 mmole) and 20% palladium hydroxide (0.2 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) for 24 hr at 30° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3-n-butyl-4-hydroxypiperidine as oil. Yield 1.4 g (87%), C9H19NO, m/z 158 (M+1) PMR (CDCl3): 0.94 (3H, t, CH3, j=8 Hz), 1.04-1.54 (7H, m, 3×CH2 & H3), 1.74 (1H, m, H5), 1.98 (2H, m, H5, & OH, D2O exchangeable), 2.22 (1H, m, H2), 2.7 (1H, m, H6), 3.12 (1H, m, H2), 3.3 (1H, m, H6), 3.46 (1H, bs, NH, D2O exchangeable), 3.98 (1H, m, H4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][C:26]#N)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[OH-:34].[K+].C(O)C.[OH-:39].[Na+]>>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][C:26]([OH:39])=[O:34])=[CH:14][CH:13]=2)=[O:33])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC(=O)O)ccc2c1=O
Yield: 87 %

Procedure:
A mixture of tert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.13 g, 0.29 mmol), 2N potassium hydroxide solution (5 mL) and ethanol (5 mL) was refluxed for 4 h. The reaction mixture was diluted with 0.1N sodium hydroxide solution (100 mL) and washed with ethyl acetate (20 mL×2). The aqueous layer was separated, acidified with 1N hydrochloric acid and extracted with ethylacetate (100 mL×2). The organic layers were combined, washed with brine (20 mL), saturated aqueous sodium hydrogencarbonate (50 mL) and brine (50 mL), dried over, anhydrous magnesium sulfate and concentrated under reduced pressure to give (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)acetic acid (0.36 g, 87%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:30]12[CH2:37][C@H:33]([C@H:34]([OH:36])[CH2:35]1)[CH2:32][NH:31]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:31]5[CH2:32][C@@H:33]6[CH2:37][C@H:30]5[CH2:35][C@H:34]6[OH:36])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O[C@@H]1C[C@@H]2C[C@H]1CN2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4C[C@H]5O)cn3)nc2n1C1CCCC1
Yield: 60 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with (1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-ol following amide formation method 3 which gave 7-cyclopentyl-2-(5-((1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (40 mg) in 60% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.51-9.43 (m, 0.3H, Rotamer) 9.43-9.35 (m, 0.7H, Rotamer) 8.87 (s, 1H) 8.66-8.60 (m, 0.3H, Rotamer) 8.60-8.52 (m, 0.7H, Rotamer+1H) 7.94-7.84 (m, 1H) 6.48 (s, 1H) 4.86-4.75 (m, 1H) 4.75-4.71 (m, 0.3H, Rotamer) 4.32-4.25 (m, 0.7; H, Rotamer) 4.21-4.13 (m, 0.7H, Rotamer) 4.08-4.02 (m, 0.3H, Rotamer) 3.61-3.50 (m, 1H) 3.15 (s, 6H) 3.10-3.01 (m, 1H) 2.93-2.83 (m, 0.7H, Rotamer) 2.78-2.67 (m, 0.3H, Rotamer H) 2.65-2.50 (m, 3H) 2.36-2.20 (m, 1H) 2.15-1.99 (m, 4H) 1.99-1.88 (m, 1H) 1.80-1.65 (m, 2H) 1.59 (none, 2H). HR-MS (m/z MH+) 490.26 RT 4.34 min
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 73 (303 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 341 mg (83%) of white solids. M.P. 262° C. 1H NMR (DMSO-d6): δ 3.57 (s, 3H), 3.64 (m, 4H), 3.91 (m, 4H), 7.16 (m, 1H), 7.50 (d, J=3.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.79 (m, 2H), 7.86 (s, 1H). EIMS m/z 414 (M+1). Anal. (C20H17ClN4O2S) C,H, N.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:17][NH:18][C:19]([NH2:21])=[O:20])[C:7]2=[O:15]
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(N)=O)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, semicarbazide hydrochloride