Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([OH:26])=O.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][C:24]([C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][C:12]3[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)[C:10]=2[C:2]=1[CH3:1])=[O:26]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c12
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 5-methyl-4-{2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid and N1,N1-dimethyl-propane-1,3-diamine.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([Cl:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:13]=2)[N:8]=1>C1COCC1>[CH:1]1([C:24]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([Cl:6])[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:15]3[Cl:23])([C:26]2[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=2)[OH:25])[CH2:3][CH2:2]1
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M in THF, 0.6 mL, 0.3 mmol) was added dropwise to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (57.3 mg, 0.15 mmol, Intermediate 2: step b) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes, then the ice bath was removed and the mixture was stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-4% MeOH-DCM) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=1.71 Hz, 1H), 8.03 (d, J=8.80 Hz, 1H), 7.66 (dd, J=1.96, 8.80 Hz, 1H), 7.46-7.61 (m, 4H), 7.39-7.46 (m, 2H), 7.30 (d, J=0.98 Hz, 1H), 5.82 (s, 1H), 3.14 (s, 3H), 1.63-1.74 (m, 1H), 0.53-0.71 (m, 2H), 0.19-0.42 (m, 2H); MS m/e 424.0 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OCC)=O>C(Cl)Cl.C1COCC1>[CH:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:16]2)=[O:12])=[O:5]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CNCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
{2-[(1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]ethyl}-carbamic acid tert-butyl ester (35 mg, 0.068 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 h. Solvent and excess TFA was removed by evaporation, and to the residue were added THF (3 mL), triethylamine (0.050 mL, 0.34 mmol), and ethyl formate (3 mL). The resulting mixture was refluxed for 4 days. After cooling to r.t., solvent was evaporated. The residue was partitioned between EtOAc and 0.1 M HCl. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 11.4 mg of the title compound as a light yellow solid. MS: (+) m/z 443.37 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](I)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]1([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([S:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C:5]4[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=4)=[O:28])=[CH:10][CH:11]=3)(=[O:17])=[O:16])[CH:19]=2)[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(C3CC3)c3ccccc32)cc1
Temperature: 100 °C
Yield: 59.3 %

Procedure:
Combine N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (0.50 g, 0.94 mmol), cyclopropylboronic acid (0.24 g, 2.8 mmol), tricyclohexylphosphine (0.05 g, 0.18 mmol), potassium phosphate (0.70 g, 3.30 mmol), and palladium acetate (0.02 g, 0.09 mmol) in a mixture of toluene (15 mL) and water (0.4 mL). Heat to 100° C. under nitrogen for 18 hours, filter through celite, and wash solids with EtOAc. Wash EtOAc with saturated NaHCO3 (30 mL), then dry with Na2SO4, and concentrate under vacuum. Purify by flash column on silica gel eluting with 0-50% EtOAc in hexanes to give the title compound (0.25 g, 60%). MS (ES) 449.2 (M+1)+, 447.4 (M−1)−.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[C:13]([O:26][CH3:27])[CH:14]=[C:15]([CH2:24][NH2:25])[C:16]=1[NH:17]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40]1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:29]([CH2:28][C:12]1[C:11]2[S:10][C:9]3[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:8]=3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:17]([C:39](=[O:46])[CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:16]=2[C:15]([CH2:24][NH2:25])=[CH:14][C:13]=1[O:26][CH3:27])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C(=O)CCCC(=O)O
Temperature: 0 °C
Yield: 71.1 %

Procedure:
A mixture of 360 mg (0.67 mmol) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-4-yl)acetate, 91.7 mg (0.80 mmol) of glutaric anhydride and. 63.7 mg (0.80 mmol) of pyridine in 5 ml of toluene was treated with 10 mg of N,N-dimethylaminopyridine. The mixture was heated to 110° under argon for 48 hours and then poured into ice-water, whereupon the mixture was acidified with 1N hydrochloric acid and exhaustively extracted with methylene chloride. The organic phase was dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with chloroform/methanol (9:1), whereupon 310 mg (71%) of 5-(4-benzyloxycarbonylmethyl-6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-10yl)-5-oxo-pentanoic acid were obtained as a white solid of m.p. 65°-68°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH:2]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH2:1])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(N)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)-aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]([CH3:40])([CH3:39])[CH:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][CH3:25])[CH:18]=[C:17]2[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=1[O:37][CH3:38])O)([OH:10])=[O:9].C([SiH](CC)CC)C.O>C(Cl)(Cl)(Cl)Cl>[C:8]([C:11]([CH3:39])([CH3:40])[CH2:12][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][CH3:25])[CH:18]=[C:17]2[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=1[O:37][CH3:38])([OH:10])=[O:9]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C(O)C(C)(C)C(=O)O)ccc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)(C)C(=O)O)ccc21
Reaction time: 0.58 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (1.25 g) was added slowly to a stirred solution of methyl 4-[5-(2-carboxy-1 hydroxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate 0.5 g) and triethylsilane (0.128 g) in carbon tetrachloride (7 ml) under an atmosphere of nitrogen. After 35 min, the mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed (water (4 times), brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 90:10:2 toluene:ethyl acetate:acetic acid, to give methyl 4-[5-(2-carboxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate as an oil (0.27 g, 56%): partial NMR (250 MHz, DMSO-d6): 0.82(t, 3H, CH2CH3), 1.02(s, 6H, C(CH3)2), 1.68(m, 2H, CH2CH3), 291(s, 2H, C(CH3)2CH2), 3.82(s, 3H, OCH3), 3.89(s, 3H, OCH3), 4.01(m, 4H, NCH2, ArCH2Ar'), 12.15(br s, about 1H, COOH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].C([Li])CCC.[F:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CCCCCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][F:17]
Reactant: C#CCCOC1CCCCO1
Reactant: FCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Product: FCCCCCCC#CCCOC1CCCCO1
Yield: 43.9 %

Procedure:
Repetition of the procedure described in Example 3 using 0.7992 g (5.06 mmol) of 3-butyn-1-yl tetrahydropyranyl ether, 3.6 mL (5.06 mmol) of 1.39M n-butyl lithium in hexane and 1.117 g (6.07 mmol, 1.2 eq) of 6-fluoro-1-bromo-hexane followed by purification by flash chromatography affords 10-fluoro-3-decyn-1-yl tetrahydropyranyl ether (570 mg, 44%) as a clear colorless oil: Rf=0.58 hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-2950 (alcane CH); and 1H-NMR (CDCl3) δ1.20-1.95 (m, 14H), 2.15 (m, 2H), 2.45 (m, 2H), 3.65 (m, 4H), 4.42 (dt, J=48 Hz, 6 Hz, 2H), 4.65 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH3:16][C:17]1C([N+]([O-])=O)=CC=CC=1C(O)=O.N1C2C(=CC=CC=2)C(C(OCC)=O)=N1.[N+]([O-])(O)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: CCOC(=O)c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
The conversion of ethyl indazole-3-acid to 5-nitroindazole-3-carboxylic acid is essentially the same method as described for methyl 3-nitrobenzoic acid: Kamm, O.; Segur, J. B. Org. Syn. Coll. Vol 1. 1941, 372. Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and the reaction mixture was cooled to 0° C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 h. The mixture was stirred for an additional 1 h at 0° C. and was poured onto of crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL acetonitrile and the mixture was heated at reflux for 2 h. The mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo to provide ethyl 5-nitroindazole-3-carboxylate (53%) as a colorless solid. The ester was added to a solution of 10 N sodium hydroxide and the suspension was warmed to 60° C. After 2 h the solution was allowed to cool to room temperature and was acidified to pH ˜2. The precipitated solids were collected by filtration, washed with water, and dried to provide the acid as a light yellow solid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([CH2:15][CH3:16])([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#N.[OH-].[NH4+].[NH2:21][CH2:22]C1C=CC(C(CC)(O)C2C=CC=CC=2)=CC=1>[Ni].C(O)C>[NH2:21][CH2:22][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([CH2:15][CH3:16])([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCC(O)(c1ccccc1)c1ccc(C#N)cc1
Reactant: CCC(O)(c1ccccc1)c1ccc(CN)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCC(O)(c1ccccc1)c1ccc(CCN)cc1

Procedure:
24 g. of 4-cyano-α-ethyl-benzhydrol are dissolved in 192 ml. of ethanol, and 48 ml. of a 25% aqueous ammonium hydroxide solution and 9.6 g. of Raney-nickel are added. The reaction mixture is hydrogenated at 50° C. After the uptake of the theoretical amount of hydrogen the catalyst is filtered off, and the clear filtrate is evaporated to dryness under reduced pressure. The solid residue is recrystallized from a mixture of n-heptane and benzene to yield 17 g. of 4-aminomethyl-α-ethyl-benzhydrol melting at 97.5°-98.5° C.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CN1CCCC1=O>>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(C3CC3)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride (35 mg), 2-chloro-5-cyclopropyl-pyrimidine (46 mg), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (82 mg) in N-methylpyrrolidinone (1.5 mol) is stirred at 70° C. overnight. The crude product is purified by preparative HPLC to give the title compound. LC (method 18): tR=1.41 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[N:47]=[N:48][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:50][CH:51]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[N:47]=[N:48][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:50][CH:51]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)nn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)nn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 52.1 %

Procedure:
Following Example 210a, 207 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (0.43 mmol) and 180 mg of 330d (0.43 mmol) were reacted to give 330e as a yellow solid (156 mg, 51%). MS: [M+H]+ 697.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:14]([CH:17]=[CH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)[CH3:2].[H][H]>[Cu].C(O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OCC)o1
Agent: [Cu]
Solvent: CCO
Product: CCCCCC(=O)CCc1ccc(CCCCCCCC(=O)OCC)o1

Procedure:
IV (1.74 g, 0.0048 mole), ethanol (25 ml), and Raney copper (Ponomarev et al., J.Gen.Chem. USSR 30 (1960) 584) (0.75 g) were shaken under 80 atmospheres of hydrogen for 6 hours at 30°C. After filtration, the ethanol was distilled under reduced pressure from a water bath (60°C). Ether (30 ml) was added to the residue, and the turbid solution was filtered (G4, Celite). The ethereal solution was evaporated to dryness from a water bath (50°C) under reduced pressure, at last under 15 mm Hg. The residual oil was purified by distillation under nitrogen. 1.51 g (86%) of V was hereby obtained as an almost colorless oil, b0.2 178°-181°C, nD25 1.4700.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(Cl)Cl.[CH2:25]([N:27](CC)CC)C>CC(N(C)C)=O.[C-]#N.[Zn+2].[C-]#N>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:25]#[N:27])=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CCN(CC)CC
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 85 °C
Yield: 88 %

Procedure:
To a suspension of 6-[(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl]quinoline (1.0 g, 2.93 mmol) in DMAC (70 ml) were added zinc cyanide (413 mg, 3.52 mmol). The reaction mixture was degassed then PdCl2(dppf).CH2Cl2 (240 mg, 0.29 mmol) was added followed with triethylamine (0.828 ml) at R.T. The reaction mixture was degassed again. After heating at 85° C., the reaction mixture was filtered through a celite pad and washed with 5.0 ml of CH2Cl2. The solvents were concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 1-3% 7N N3 in MeOH:CH2Cl2 to give the desired product (740 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.28 (s, 2H) 7.55 (dd, J=8.34, 4.29 Hz, 1H) 7.81 (dd, J=8.72, 2.15 Hz, 1H) 7.99-8.04 (m, 2H) 8.33-8.37 (m, 1H) 8.91 (dd, J=4.04, 1.77 Hz, 1H) 9.41 (s, 1H) APCI (Mz+1) 288.2
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:4][N:3]=1.[C:19]([Zn]C#N)#[N:20]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([C:10]1[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:19]#[N:20])[CH:7]=1)#[N:12]
Reactant: N#Cc1cc(C=O)ccc1Oc1ccnc(Cl)c1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Oc2ccc(C=O)cc2C#N)ccn1

Procedure:
To a solution of 2-((2-chloropyridin-4-yl)oxy)-5-formylbenzonitrile (400 mg, 1.55 mmol) and dicyanozinc (182 mg, 1.55 mmol) in N,N-dimethylacetamide (DMA) (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (179 mg, 0.155 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h and filtered.
Reaction SMILES: [B-]([S+](C)C)(F)(F)F.C[O:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[CH:25]=[CH:26][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:24][CH:23]=1.[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[CH:25]=[CH:26][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1
Agent: C[S+](C)[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reaction time: 5 h

Procedure:
Boron fluoride—dimethyl sulfide complex [CAS: 353-43-5] (15.64 ml, 148.67 mmol) was added dropwise to a stirred solution of methyl 4-(4′-methoxyphenoxy)benzoate [CAS: 38342-84-6] (1.28 g, 4.9 mmol) in DCM (100 ml) cooled in an ice-water bath under nitrogen atmosphere. The resulting mixture was stirred for 5 hours. The reaction mixture was washed with water and then extracted with DCM. The organic layer was separated and dried (Na2SO4) and the solvent was evaporated till dryness. The residue was purified by column chromatography (silica gel; 0-10% EtOAc/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D24 (0.89 g, 74%).
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(O)C.[I-:29].[K+]>O>[I-:29].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)cc1
Yield: 131.7 %

Procedure:
A mixture of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2-(trans)propenyl]dimethylamine (2.2 g), α,4-dichlorotoluene (0.8 g) and ethanol (30 cc) was refluxed for 1 hour, and thereto were added water (100 cc) and potassium iodide (5.0 g). The reaction mixture was extracted with chloroform, and the chloroform layer was dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol to give crystals (3.1 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(4-chlorobenzyl)ammonium iodide.