Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])[N:14]=[C:13]([Cl:27])[CH:12]=1>CN(C)C=O>[ClH:27].[CH3:10][C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])[N:14]=[C:13]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[CH:12]=1
Reactant: Cc1cc(Cl)nc(N2CCc3ccsc3C2C)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(F)cc2C)nc(N2CCc3ccsc3C2C)n1
Product: Cl
Yield: 48 %

Procedure:
After 2-methyl-4-fluoroaniline(0.38 ml, 3.42 mmol) was added to a mixture solution of 6-methyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-4-chloropyrimidine (0.5 g, 1.8 mmol) and dimethylformamide(10 ml), 0.35 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5](I)=[CH:4][N:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: OCCCNc1nc(Cl)ncc1I
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: COCCOC
Product: OCCCNc1nc(Cl)ncc1-c1cccs1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
In accordance with procedure 3, 3-(2-chloro-5-iodopyrimidine-4-ylamino)propan-1-ol (1.38 g, 4.4 mmol) and 2-thiophenboronic acid (0.62 g, 4.87 mmol) are dissolved in 15 ml dimethoxyethane under argon, and tri(2-furyl)phosphine (104 mg, 0.45 mmol) and 1 molar Na2CO3 soln. (7.1 ml, 7.1 mmol) are added (the previously light yellow reaction mixture becomes almost colourless and turbid after the Na2CO3 addition). Argon is passed in for 15 mins. Tetrakis(triphenyl-phosphine)palladium (511 mg, 0.44 mmol) is then added and the reaction mixture is stirred for 18 hrs at 75° C. under argon (suspension). Dimethoxyethane is distilled off on the rotary evaporator, the residue treated with 250 ml ethyl acetate and 30 ml H2O, stirred vigorously for 30 mins, and the undissolved substance filtered off at the pump on a G4 frit, and washed with H2O and ethyl acetate: 372 mg residue.
Reaction SMILES: N[C@H](C(CBr)=[O:8])CC(C)C.Br.[NH:12]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C@H:13]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:33](CCl)=[O:34])[CH2:29]C(C)C)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH:12]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C@H:13]([C:21]([NH:23][CH2:24][C:25]([OH:26])=[O:8])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[CH3:29][C@H:28]([NH2:27])[C:33]([OH:34])=[O:8]
Reactant: CC(C)C[C@H](N)C(=O)CBr
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Br
Product: C[C@H](N)C(=O)O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A mixed anhydride of Z-Phe-Gly-ALa-OH (0.41 g, 0.95 mmol) was prepared and coupled to H-LeuCH2Br.HBr substantially according to the procedure described for preparation of Z-Phe-Gly-Leu-CH2Cl, above. The resulting product was crystallized from ethyl acetate:hexane to yield 0.30 g. Product was recrystallized from the same solvents to yield 0.07 g, m.p. 135.5°-138° (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.[I-].[K+]>C(O)C>[CH3:8][C:7]([CH3:10])([C:6](=[O:11])[CH:5]([CH2:23][CH:20]1[CH2:22][CH2:21]1)[C:4](=[O:12])[C:2]([CH3:13])([CH3:1])[CH3:3])[CH3:9]
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)C(=O)C(CC1CC1)C(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2,2,6,6-tetramethyl-3,5-heptanedione (18.4 g) in ethanol (100 ml) was added potassium carbonate (20.7 g) followed by cyclopropylmethyl bromide (13.5 g). The mixture was heated at reflux for 16 hours. Potassium iodide (2 g) and further cyclopropylmethyl bromide (2 g) was added to the reaction mixture and reflux continued for a further 8 hours. The reaction mixture was cooled and concentrated in vacuo. To the residue was added water and the resultant mixture was extracted with ether. The ether extracts were washed with water and dried. Concentration in vacuo gave the product as an oil which was used without further purification.
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4]C1=O.[CH3:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[N:19]3[N:20]=[C:21]([O:28][CH2:29][C:30]4[CH:31]=[N:32][C:33]([CH:36]=[CH2:37])=[CH:34][CH:35]=4)[C:22]4[C:27]([C:18]3=[N:17][N:16]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:11]=1.[OH-:38].[Na+].C(C1C=CC=CN=1)=C.N1CCC1>CN(C=O)C.O.CC(O)=O>[N:2]1([CH2:37][CH:36]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]4=[N:17][N:16]=[C:15]([C:12]5[CH:11]=[C:10]([CH3:9])[O:14][N:13]=5)[N:19]4[N:20]=3)=[CH:31][N:32]=2)[OH:38])[CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1ccc(COc2nn3c(-c4cc(C)on4)nnc3c3ccccc23)cn1
Reactant: O=C1CCC(=O)N1Br
Reactant: [OH-]
Agent: C1CNC1
Agent: C=Cc1ccccn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C(O)CN5CCC5)nc4)nn23)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1 %

Procedure:
N-Bromosuccinimide (254 mg, 1.42 mmol) was added to a stirred solution of 3-(5-methylisoxazol-3-yl)-6-(6-vinylpyridin-3-ylmethoxy)-[1,2,4]triazolo[3,4-α]phthalazine (500 mg, 1.30 mmol) in DMF (70 ml), H2O (10 ml) and AcOH (0.1 ml) and the resulting solution stirred at room temperature for 90 min and then 4 N NaOH (3 ml) was added. The mixture was concentrated under reduced pressure and then taken up in CH2Cl2 (100 ml), dried and concentrated. The mixture was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 as eluent to yield a 1:1 mixture of the vinylpyridine and the epoxide, m/z (ES+) 401 (M+H+), which was used without further purification. The crude residue was taken up in DMF (5 ml) in a sealed tube and azetidine (126 μl, 1.87 mmol) was added. The reaction was heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and then taken up in MeOH/CH2Cl2, dry loaded onto silica and purified by column chromatography on silica using 8% MeOH/CH2Cl2 containing 1% NH3 as eluent. The fractions containing the correct compound were concentrated under reduced pressure and further purified on a prep. plate eluting with 7% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (4.9 mg, 1%). 1H NMR (400 MHz, CDCl3) δ 8.82 (1H, s), 8.64 (1H, d, J=7.4 Hz), 8.21 (1H, d, J=7.4 Hz), 8.06 (1H, d, J=7.4 Hz), 7.95 (1H, t, J=7.4 Hz), 7.80 (1H, t, J=7.4 Hz), 7.55 (1H, d, J=7.4 Hz), 6.84 (1H, s), 5.68 (2H, s), 4.68 (1H, dd, J=7.7, 3.5 Hz), 3.38-3.23 (4H, m). 2.87 (1H, dd, J=10.9, 3.5 Hz), 2.70 (1H, dd, J=10.9, 7.7 Hz), 2.60 (3H, s), 2.10 (2H, quintet, J=6.3 Hz). m/z (ES+) 457 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[CH:14][N:15](C)C)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22]N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:20])([CH3:19])[C:11]2[NH:22][N:15]=[CH:14][C:12]=2[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC(C)(C)C1=O
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.35 g, 22 mmol) in methanol (15 mL) was added hydrazine hydrate (1.2 mL, 1.1 equiv). The solution was stirred at room temperature overnight and concentrated to give 5.3 g (94%) which was used without purification. Mass spec.: 252.19 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:12](O)[CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:15][CH2:14][CH2:13][CH2:12][O:6]2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc(C2OCCCO2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 3-bromo-5-methoxybenzaldehyde (3.93 g, 18.2 mmol), propane-1,3-diol (1.6 mL, 21.8 mmol) and p-toluenesulfonic acid monohydrate (0.104 g, 0.54 mmol) in anhydrous toluene (100 mL) was brought to reflux for 18 h under nitrogen. During this time water was removed using a Dean-Stark apparatus. After this time the reaction was cooled to rt, washed with 5% aqueous Na2CO3 solution (50 mL) and dried over anhydrous Na2SO4. The reaction was concentrated under reduced pressure to give 2-(3-bromo-5-methoxyphenyl)-1,3-dioxane (4.80 g, 96%) as a brown oil.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[S:8][C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=1)[CH3:6])(=O)[CH3:2].[Br:14]CC([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>O.C(#N)C.CCOCC>[Br-:14].[CH3:13][C:9]1[S:8][C:7]2[CH:5]([CH3:6])[O:4][C:1]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:2][N+:11]=2[C:10]=1[CH3:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)OC(C)c1nc(C)c(C)s1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: Cc1sc2[n+](c1C)C=C(c1ccccc1)OC2C
Product: [Br-]
Reaction time: 3.5 h
Yield: 26.3 %

Procedure:
1-(4,5-Dimethyl-2-thiazolyl)ethyl acetate (1.28 g, 6.4 mmole), 2-bromo-1-phenyl-1-ethanone (1.28 g, 6.4 mmole), and acetonitrile (0.5 mL) were heated at 105 C. with stirring for 3.5 hr. The mixture was diluted with water (60 mL), filtered with water washes (20 mL), and the filtrate was extracted with ether (30 mL). The aqueous phase was evaporated to dryness in vacuo yielding 1.8 g crude product, which was dissolved in acetonitrile, diluted with ether, and stored at room temp. for several days to produce needle-like crystals which were recrystallized from methanol/acetonitrile/ether to give 0.57 g of the title compound, mp 236 C. (dec.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.[CH3:22][O:23][C:24](=[O:33])[C:25](=[CH:30]OC)[C:26](OC)=[O:27].C[O-].[Na+:36]>CO>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[N:16]=[C:26]([O-:27])[C:25]([C:24]([O:23][CH3:22])=[O:33])=[CH:30][N:17]=2)=[N:7]1.[Na+:36]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]

Procedure:
2.5 g of 1-(2-fluorobenzyl)-1H-indazole-3-carboximidamide hydrochloride (1:1) (1-2-3×HCl, 8.20 mmol, 1 eq.), 1.43 g of dimethyl(methoxymethylidene)propanedioate (8.20 mmol, 1 eq.) and 50 ml of methanol and 443 mg of sodium methanolate were stirred under nitrogen atmosphere at 60° C. bath temperature for 24 hours. The clear yellowish solution turned into a suspension which was filtered off. The crystals were washed with cold methanol to yield 1.64 g (4.1 mmol, 50%) of the analytically pure target compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([CH:13]=[O:14])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>ClCCl>[CH3:24][O:25][CH2:26][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(C=O)ccc(O)c12
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C=O)c2cccc(C)c12
Yield: 75.5 %

Procedure:
18 g of 4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 15 g of N,N-diisopropylethylamine were dissolved in 200 ml of dichloromethane, in which 9.3 g of chloromethyl methyl ether was gradually dropped under ice-cooling conditions. After agitation at room temperature overnight, the reaction solution was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 16.8 g of the captioned compound as light brown crystals.
Reaction SMILES: C(B1O[C:8]([CH3:10])([CH3:9])[C:5]([CH3:7])(C)O1)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=CC(Br)=C[N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]>CN(C)C=O.O>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:9][C:8]([CH:5]=[CH2:7])=[CH:10][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(-n2ncc(C(=O)OCC)c2C)c(Cl)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Vinylboronic acid pinacol ester (1.37 ml), tripotassium phosphate (3.85 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (301 mg) were added to a solution of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.52 g) described in Reference Example 44(2) in N,N-dimethylformamide (36 ml), and the mixture was stirred at 100° C. for seven hours. The reaction solution was cooled to room temperature, diluted with water, filtered through Celite and the filtrate was extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-vinylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.67 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=O)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(O)(=O)C>[CH:22]1([C:20]2[N:12]([C@H:10]3[CH2:11][C@H:8]([NH2:7])[CH2:9]3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncccc2NC(=O)C2CC2)C1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@H](n2c(C3CC3)nc3cccnc32)C1
Temperature: 105 °C
Yield: 53.9 %

Procedure:
Tert-butyl(trans-3-((3-(cyclopropanecarboxamido)pyridin-2-yl)amino)cyclobutyl)carbamate (1.27 g, 3.67 mmol, was dissolved in acetic acid (300 mL) and heated at 105° C. After 4½ hours, trifluoroacetic acid (1 mL) was added and the reaction stirred at 105° C. After heating for an additional 5 hours, the reaction was evaporated to dryness under reduced pressure. The crude product was free based by partitioning between dichloromethane and saturated aqueous sodium bicarbonate. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (0-10% methanol in dichloromethane gradient) to give trans-3-(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutanamine (0.579 g, 2.54 mmol, 53.9% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][O:20][CH3:21])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].C([Sn](CCCC)(CCCC)[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)CCC.C(OCC)(=O)C>O1CCOCC1.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>[CH3:21][O:20][CH2:19][C@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)[CH:11]=1)[C:5]([OH:7])=[O:6])=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COC[C@H]1CCCN1C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 95 °C
Yield: 75.7 %

Procedure:
To a solution of (R)-methyl 3-bromo-5-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzoate (Step H (1), 350 mg, 1.0 mmol) in dioxane (5 mL) were added Pd(PPh3)4 (173.5 mg, 0.15 mmol) and 2-(tributylstannyl)oxazole (1.8 g, 5.0 mmol) above made and the reaction mixture was stirred at 95° C. with sealed cap for 16 h. Ethyl acetate (200 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 250 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 1.75-2.11 (4H, m), 3.08 (1H, brd s), 3.38 (3H, s), 3.50 (1H, m), 3.63 (2H, s), 3.83 (3H, s), 4.43 (1H, s), 7.24 (1H, s), 7.73 (1H, s), 8.22 (1H, s), 8.35 (1H, s), 8.71 (1H, s). MS (ESI) (M+H)+ 345.26.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH2:20][C:21]#N)[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-:31].[NH4+].[CH2:33]([OH:35])[CH3:34]>>[CH2:33]([O:35][C:21](=[O:31])[CH2:20][C:19]1[C:12]2[O:11][C@@H:10]([CH2:9][NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][O:14][C:13]=2[CH:16]=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])[CH3:34]
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCc1c([N+](=O)[O-])ccc2c1O[C@@H](CNCc1ccccc1)CO2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCOC(=O)Cc1c([N+](=O)[O-])ccc2c1O[C@@H](CNCc1ccccc1)CO2
Temperature: 75 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
A 100 mL round bottomed flask equipped with a magnetic stir bar is charged {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetonitrile (5.00 g, 14.5 mmol) and 95% ethanol (7.5 mL). To the stirred solution is added 95% sulfuric acid (5.0 mL, 89.0 mmol). The flask is immersed in an oil bath and heated to 75° C. for 4 days. The solution is cooled to room temperature and absolute ethanol (42.5 mL) is added. The reaction mixture is adjusted to pH 10 by the addition of 28% ammonium hydroxide (˜12 mL), and the resulting slurry is stirred for 3 h. The precipitate is removed by vacuum filtration and the volatiles are evaporated giving crude title compound (6.02 g, 106%) as a red syrup. LCMS (Basic Method): 2.33 min, 387 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].C(N(CC)CC)C.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>C(#N)C>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-3 step (ii) (240 mg), triethylamine (0.12 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (204 mg) were dissolved in acetonitrile (5 ml), and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 35 mg (9%); mp 218-219° C., MS APCI+ve 493 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:31]3[CH:32]=[CH:33][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)O)cc3)c1)N2
Yield: 76.9 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), 4-carboxyphenylboronic acid (2.5 g, 15.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.1 mmol) in dioxane (10 mL) was added 2 M sodium carbonate solution in water (10 mL, 20 mmol). The resulting mixture was subjected to microwave irradiation for 60 min at 110° C. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-carboxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.4 g, 80%) as a white solid: LC/MS m/e calcd for C27H27NO4 (M+H)+: 430.52, observed: 430.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:14][N:13]([C:15]3[N:16]4[C:20]([N:21]=[C:22]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=35)=[CH:19][CH:18]=[N:17]4)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:11]2[CH2:12][N:13]([C:15]3[N:16]4[C:20]([N:21]=[C:22]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=35)=[CH:19][CH:18]=[N:17]4)[CH2:14]2)[OH:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 200 mg (0.53 mmol) (4-methoxy-phenyl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 3 mL MeOH was added 20 mg (0.53 mmol) sodium borohydride and the mixture was stirred at room temperature for 30 minutes. 1 mL saturated brine was added and the mixture extracted with DCM (2×5 mL), the organic layers were combined and dried over sodium sulphate. After filtration the solvent was evaporated to give the desired product.