Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:12][C:11]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:2]([O:6][C:7]([N:9]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37% w/w, 40 μL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (45 mg, 84%).
Reaction SMILES: Br[C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH:21]3[CH2:23][CH2:22]3)[CH:14]=2)[C:6]1=[O:24].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:7]2[C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=3[NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)[C:6]2=[O:24])=[CH:14][C:15]=1[CH:21]1[CH2:23][CH2:22]1)#[N:18]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C3CC3)c2)C(=O)N1Cc1ccc(F)cc1Br
Product: COC(=O)c1ccc(Nc2cc(F)ccc2CN2C(=O)N(c3ccc(C#N)c(C4CC4)c3)C(=O)C2(C)C)cc1

Procedure:
The further reaction of 158.2 with methyl 4-aminobenzoate was effected under conditions as described above for the preparation of example 1, stage 3. 158 with the molecular weight of 526.20 (C30H27F4N4O4) was obtained; retention time Rt=2.19 min. [B]; MS (ESI): 527.28 (MH+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:22]2[C@@H:27]([NH2:28])[CH:26]3[CH2:29][CH2:30][N:23]2[CH2:24][CH2:25]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:37][O:38][C:39]([C:42]1[CH:43]=[CH:44][C:45]([O:50][CH3:51])=[C:46]([CH:49]=1)[CH:47]=O)([CH3:41])[CH3:40]>C(Cl)Cl>[CH3:51][O:50][C:45]1[CH:44]=[CH:43][C:42]([C:39]([O:38][CH3:37])([CH3:40])[CH3:41])=[CH:49][C:46]=1[CH2:47][NH:28][C@H:27]1[CH:26]2[CH2:29][CH2:30][N:23]([CH2:24][CH2:25]2)[C@H:22]1[CH:21]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(C)(C)OC)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C)(C)OC)cc1CN[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 43.9 %

Procedure:
Sodium triacetoxyborohydride (152 mg, 0.707 mmol) was added to a solution of (2S,3S)-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-amine(135 mg, 0.462 mmol) and 5-(1-methoxy-1-methylethyl)-2-methoxybenzaldehyde prepared in example 1 (92 mg, 0.442 mmol) dissolved in methylene chloride (4 ml) at room temerature, and the resulting solution was stirred for 4 h. The reaction mixture was diluted with methylene chloride, and washed with aq. sodium bicarbonate solution and brine. The extracts were dried over magnesium sulfate, and concentrated by evaporation. The residual oil was purified by crystallization from methylene chloride to yield analytically pure sample of the title compound as a white crystal (94 mg, 42%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([C:19]([N:10]2[CH2:11][CH2:12][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:8]([OH:13])[CH2:9]2)=[O:20])[CH2:18][CH2:17]1
Reactant: O[C@@H]1CNCC[C@@H]1c1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@H](c2ccccc2)[C@H](O)C1
Reaction time: 0.25 h

Procedure:
cis-4-Phenyl-3-piperidinol (9.0 g, 50.8 mmoles, described in Example 9) is dissolved in methylene chloride (200 ml) and a 30% solution of sodium hydroxide (100 ml) is added. Cyclopropanecarboxylic acid chloride (5.72 g, 55.0 mmoles) is added dropwise to the cooled solution (10° C.) and stirring is continued for 15 minutes. The organic phase is separated, washed with brine, dried (MgSO4) and evaporated. The residue is crystallized from ethyl acetate-ether to give cis-1-cyclopropylcarbonyl-4-phenyl-3-piperidinol, mp 175°-177° C.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([O:21]C)=O)[C:12]=3[N:11]=2)[CH:7]=[CH:8][CH:9]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:1])=[O:21])[C:12]=3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3cccc(OC)c3)nc12
Product: COc1cccc(-c2nc3c(C(N)=O)cccc3[nH]2)c1
Yield: 46 %

Procedure:
Following standard procedure C, a liquid ammonia solution of methyl 2-(3′-methoxyphenyl)-1-H-benzimidazole-4-carboxylate (203 mg, 0.596 mmol) was heated under constant volume. The solid residue was recrystallised from methanol to give the pure product (73.5 mg, 46%). mp 223-225° C.; Found C 67.52 H 4.91 N 15.62 C15H13N3O2 Requires C 67.42 H 4.87 N 15.73; vmax(cm−1) 3408.59, 3388.94, 3168.65, 1662.05, 1625.86, 1603.39; δH 3.99 (3H, s, OCH3), 7.22-7.27 (1H, d),7.43-7.51 (1H, t), 7.58-7.66 (1H, t), 7.85-8.01 (5H, m), 9.4-9.5 (1H, br s), 13.5 (1H, br s); m/z (EI) 267 (M+), 250.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:19]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 81 %

Procedure:
2,5-Dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5dimethylbenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 102°-104° C., yield 81%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([NH:1][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (25.9 g, 98.6 mmol) and DIPEA (20.6 mL, 15.4 g, 118 mmol) were dissolved in 500 mL of DCM. Trimethylacetyl chloride (12.7 mL, 12.5 g, 103 mmol) was added dropwise at 0° C. and the solution was stirred for 3 h at 0° C. and 1 h at room temperature. The pink solid was collected by filtration, washed with H2O and dried in vacuo. Yield: 33.1 g (97%); MS (ESI) (M+H)+=348.05.
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:43])[CH2:7][N:8]([C:15](=[O:42])[C@H:16]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])[NH:17][S:18]([C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:24][C:23]=2[CH:22]=1)(=[O:20])=[O:19])[CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)C.[OH-].[Na+]>CO>[N:1]#[N:2].[CH:22]1[C:23]2[S:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:31][C:32]=2[CH:33]=[CH:34][C:21]=1[S:18]([NH:17][C@H:16]([C:15]([N:8]([CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][C:6]([OH:43])=[O:5])=[O:42])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:19])=[O:20]
Reactant: CCOC(=O)CN(CC1CCCO1)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)N(CC(=O)O)CC1CCCO1
Reaction time: 10 h
Yield: 69.8 %

Procedure:
A solution of 4.8 g of N2 -(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethyl ester in 15 ml of methanol and 15 ml of 2N-NaOH solution was warmed to 40° C. and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10 : 9 : 1). The main fraction was evaporated to dryness and washed with ethyl ether to give 3.2 g (80 percent) of N2 -(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine as an amorphous solid. I.R. (KBr): 3350, 1640, 1250 cm-1
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:22][CH3:23])(=O)=O.O>C(#N)C>[CH2:22]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH3:23]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C=O)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Vanillin (10 g., 66 mmol) in acetonitrile (100 ml) was treated with finely-powdered, anhydrous potassium carbonate (12 g., 87 mmol) with vigorous stirring to yield a mobile suspension. Diethyl sulfate (11 ml, 84 mmol) was added at room temperature. The suspension was brought to reflux, becoming quite thick after 10 minutes, but thinning again after 20 minutes. Refluxing was continued for 48 hours, at which point water (5 ml) was added. After an additional 2 hours of reflux, the mixture was cooled and treated with 500 ml ice water. Stirring at 0° for several hours produced a granular precipitate which was filtered off and washed with water. Air drying afforded 11.5 g. of the product (97%) as an off-white solid melting at 61°-62.5° C. NMR and IR data are listed in Tables 3 and 7. ##STR25##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:15]([CH3:17])[CH3:16]
Reactant: CN(C)C(=O)CCc1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCCc1c[nH]c2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To an argon purged 250 mL round bottom flask fitted with condenser and magnetic stirbar containing 53 (1.283 g, 4.35 mmol) was added lithium aluminum hydride (412 mg, 10.86 mmol). Anhydrous tetrahydrofuran (15 mL) was added resulting in gas formation. The flask was placed in an oil bath and heated to 65° C. and stirred for 16 hours under argon. The reaction was cooled to room temperature and quenched with water (1.1 mL), 3N sodium hydroxide (1.7 mL) and water (3.3 mL) sequentially. The mixture was filtered to remove the white solid and the pale yellow filtrate concentrated to afford a pale yellow oil. Drying under high vacuum afforded a pale yellow solid, compound 54. Yield: 1.193 g of pale yellow solid (97.5%). 1H NMR (DMSO) δ 7.65-7.64 (d, 1H, J=1.5), 7.30-7.27 (d, 1H, J=8.7 Hz), 7.167 (s, 1H), 7.14-7.09 (q, 1H, J=6.9, 8.4 Hz), 2.67-2.62 (t, J=7.5, 2H), 2.25-2.20 (t, J=7.5 Hz, 2H), 2.12 (s, 8H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][C@@H:29]([CH3:32])[CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][C@@H:29]([CH3:32])[CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: C[C@H](N)CO
Product: CCn1c(=O)c(C(=O)N[C@@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 51 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.162 mmol) and (2S)-2-amino-1-propanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1S)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (33 mg, 51% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.27 (d, J=7.6 Hz, 1 H), 8.50 (s, 1 H), 7.33 (s, 1 H), 7.16-7.12 (m, 2 H), 7.04-6.98 (m, 2 H), 4.27 (m, 6 H), 3.78 (dd, J=11.2, 3.6 Hz, 1 H), 3.65 (dd, J=11.2, 6 Hz, 1 H), 1.29 (d, J=6.8 Hz, 3 H), 1.19 (m, 3 H); MS m/z 400 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)=O.[C:19]1([CH:25]2[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:19]1([CH:25]2[CH2:29][CH2:28][N:27]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]([O:9][C:10]4[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=4)=[N:7][CH:8]=3)[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
Combine 4-(5-formyl-pyridin-2-yloxy)-benzamide (100 mg, 0.413 mmol), (±)-3-phenyl-pyrrolidine (78 mg, 0.318 mmol), sodium triacetoxy-borohydride (101 mg, 0.477 mmol), AcOH (0.018 mL, 0.318 mmol) in CH2Cl2 (5 mL). Stir at rt overnight. Pour the reaction mixture onto an SCX column, eluting with ammonia (2M in methanol) followed by chromatography [CH2Cl2:ammonia (2.0 M in methanol) 20:1] to provide the title compound (43 mg, 36%). Mass spectrum (ion spray): m/z=373.9 (M+1); 1H NMR (DMSO-d6): 8.09 (d, J=1.9 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.6 Hz, 2H), 7.82 (dd, J=2.2 Hz, 8.6 Hz, 1H), 7.30 (bs, 1H), 7.27-7.24 (m, 4H), 7.17-7.12 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 3.61 (dd, J=13.1 Hz, 19.5 Hz, 2H), 3.33-3.24 (m, 1H), 2.88 (t, J=8.3 Hz, 1H), 2.66 (t, J=7.0 Hz, 2H), 2.42 (t, J=8.3 Hz, 1H), 2.28-2.18 (m, 1H), 1.79-1.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([CH3:21])[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1C
Temperature: 150 °C

Procedure:
A 10˜20 mL process vial was charged with 500 mg 6-Methoxy-5-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one in 15 mL POCl3. The vial was heated at 150° C. for 30 min under microwave irradiation. After cooling, POCl3 was removed under reduced pressure. MeOH was carefully added to the residue during which the precipitate was formed. The solid was collected as crude product for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CC(O)=O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)[CH2:26][CH2:27]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (100 mg, 0.57 mmol), 1-[2-(4-Nitrophenyl)ethyl]piperazine (134 mg, 0.51 mmol) in 60 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (362 mg, 1.71 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-methoxy-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.14 (d, J=8.6 Hz, 2H), 7.35˜7.47 (m, 3H), 6.79˜6.85 (m, 2H), 3.12 (s, 3H), 2.48˜2.96 (m, 16H). MS m/z: 395 (M+1)+. (0.052 μM)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[CH:14]([CH3:16])[CH3:15].[NH3:24]>C1(C)C=CC=CC=1>[NH2:24][C:13]([CH:14]([CH3:16])[CH3:15])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(N)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.8 g of p-toluenesulphonic acid×4 H2O are added to 500 g (3.16 mol) of ethyl isobutyrylacetate in 1,500 ml of toluene p.a., the mixture is saturated with ammonia gas while stirring at room temperature and allowed to stand overnight. It is then heated under reflux in a water separator and ammonia gas is continuously introduced until the calculated amount of water has separated (47 ml of water after reflux for 8 hours). The mixture is allowed to cool overnight, and the precipitate which has deposited is filtered off with suction and washed with toluene. The combined toluene phases are washed several times with water, dried using sodium sulphate, concentrated in vacuo and distilled in a high vacuum.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=O)=[N:5]1)([CH3:3])[CH3:2].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([NH:40][CH2:39][CH2:38][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: NCCN1CCCC1
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)c2ccn(C(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
(±)-3-(1-Isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (220 mg, 0.50 mmol) and 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) were suspended in anhydrous DMF (6 mL) N,N-Diisopropylethylamine (0.2 mL, 1.2 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (300 mg, 0.79 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated completion of reaction (LC/MS [M+H]+ 534.6). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH to afford the title compound (230 mg, 86%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.20 (br, 1H), 8.81 (d, 1H, J=2.8 Hz), 8.03 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.0 and 8.0 Hz), 6.16 (s, 1H), 4.52 (septet, 1H, J=6.8 Hz), 4.34 (br, 1H), 3.90 (s, 3H), 3.58 (m, 2H), 3.52-3.40 (m, 4H), 3.20-2.80 (m, 4H), 2.63 (t, 2H, J=6.8 Hz), 2.54 (br s, 4H), 2.20 (br s, 2H), 2.02 (m, 2H), 1.78 (br s, 4H), 1.47 (d, 6H, J=6.8 Hz). MS (ES) m/z 534.6 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 112.3 %

Procedure:
A mixture of 1-bromo-3,5-dimethylbenzene (25.0 g, 135 mmol), NBS (24.0 g, 135 mmol) and BPO (1.30 g) in CCl4 (250 mL) was refluxed for 6 h. After cooled to room temperature, the mixture was filtered, and the filtrate was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuum to give 40.0 g of crude product 1-bromo-3-(bromomethyl)-5-methylbenzene.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)[CH3:2].[F:24][C:25]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:26]=1[C:27]([NH:29][NH2:30])=O>C1(C)C(C)=CC=CC=1>[C:20]([C:5]1[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][N:8]2[C:4]=1[C:1]([CH3:2])=[N:30][N:29]=[C:27]2[C:26]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:25]=1[F:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: NNC(=O)c1cc(F)ccc1F
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C(C)(C)C
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nnc(C)c3c2C(C)(C)C)cc1
Temperature: 180 °C
Yield: 53.4 %

Procedure:
5-Acetyl-4-tert-butyl-3-(4-methylphenyl)sulfonyloxypyrazole (0.4 g, 1.19 mmol) was dissolved in xylene (20 ml) with 2,5-difluorobenzoic hydrazide (0.225 g, 1.31 mmol) and heated under reflux for 14 h. The xylene was removed by evaporation and replaced with Dowtherm A (15 ml) and heated at 180° C. for 4 h. The reaction mixture was allowed to cool to room temperature and poured directly onto a silica column and eluted with dichloromethane then 1-5% ethyl acetate/dichloromethane to give the required product (0.3 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.64 (9H, s), 2.42 (3H, s), 3.11 (3H, s), 7.11-7.83 (8H, m); MS (ES+) m/e 473 [MH]+.