Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:4]2[CH:3]=[CH:2][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 31.4 %

Procedure:
Palladium hydroxide (20 mg) was added to solution of 6-chloro-4-(4-nitrophenoxy)pyrimidine (300 mg) in an ethyl acetate (10 ml)-methanol (10 ml) mixed solvent, and the mixture was stirred for 13 hours at room temperature under a hydrogen atmosphere at normal pressure. The reaction solution was filtered, the filtrate was concentrated, and the residue was passed through NH silica gel (Fuji Silicia Chemical). Elution was performed with a solvent (ethyl acetate:hexane=1:2) to obtain 70 mg of 4-(4-aminophenoxy)pyrimidine. The title compound (107 mg) was obtained from the obtained 4-(4-aminophenoxy)pyrimidine (70 mg) and 4-methoxyphenyl isocyanate, in the same manner as Example 10.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[O:34](S(C(F)(F)F)(=O)=O)[S:35]([C:38]([F:41])([F:40])[F:39])(=O)=[O:36].CCOC(C)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([O:19][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:34])=[C:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(-c2c(O)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 1-benzyl-6-chloro-4-hydroxy-3-(3-methyl-isoxazol-5-yl)-1H-quinolin-2-one (1.00 g, 2.73 mmol) and Et3N (0.57 ml, 4.10 mmol) in 20 ml of DCM under at −78° C. was added Tf2O (0.50 ml, 3.0 mmol) slowly under Ar. The mixture was warmed to rt. Treated with 150 ml of EtOAc, the mixture was washed with H2O (4×50 mL), brine (40 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure gave 1.35 g (99%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 7.95 (d, 1H, J=2.3 Hz), 7.55 (dd, 1H, J=9.0, 2.3 Hz), 7.27-7.37 (m, 4H), 7.21 (d, 2H, J=8.3 Hz), 7.17 (s, 1H), 5.60 (s, 2H), 2.42 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H14ClF3N2O5S, 499.0 (M+H), found 499.0.
Reaction SMILES: Cl.C([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)C.[CH2:23]([N:25]([CH2:40][CH3:41])[C:26](=[O:39])[C:27](=[N:31]NC1C=CC=CC=1)[C:28](=O)[CH3:29])[CH3:24].[CH3:42]C(O[Na])=O>[Zn].C(O)(=O)C>[CH2:40]([N:25]([CH2:23][CH3:24])[C:26]([C:27]1[NH:31][C:9]2[CH2:10][C@@:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C@H:6]([CH2:7][C:8]=2[C:28]=1[CH3:29])[CH2:5][N:4]([CH3:42])[CH2:13][CH2:12]3)=[O:39])[CH3:41]
Reactant: CC(=O)O[Na]
Reactant: CCN(CC)C(=O)C(=NNc1ccccc1)C(C)=O
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CN(C)CC[C@@]1(c1cccc(OC)c1)C2
Yield: 14.7 %

Procedure:
3 g (9.3 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.92 g (11.2 mmol) of N,N-diethyl-2-phenylhydrazono-3-oxobutyramide, 0.92 g (11.2 mmol) of CH3COONa, 2.8 g (42.8 mmol) of zinc dust and 9.3 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (AcOEt/MeOH/conc. NH4OH 90:10:1; Rf=0.27) yielding 0.56 g of the title compound. M.p. (.HCl)=250° C. dec. C25H35N3O2I.R. (KBr) (hydrochloride): 3410, 3200, 2915, 2510, 1605, 1580 cm-1.
Reaction SMILES: [C:1](Cl)(=O)C.[CH2:5]([C:7]1[C:8]([O:18]C)=[N:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12](NO)=N)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:17][C:10]1[NH:9][C:8](=[O:18])[C:7]([CH3:5])=[CH:16][C:11]=1[C:12]1[CH:1]=[C:24]([CH:23]=[CH:22][CH:21]=1)[C:25]#[N:20]
Reactant: CC(=O)Cl
Reactant: c1ccncc1
Reactant: CCc1cc(C(=N)NO)c(C)nc1OC
Product: Cc1[nH]c(=O)c(C)cc1-c1cccc(C#N)c1
Temperature: 98 °C
Yield: 20 %

Procedure:
Acetyl chloride (121 μL, 1.70 mmol) is added drop-wise to a mixture of 5-ethyl-N-hydroxy-6-methoxy-2-methylnicotinamidine (formed on 1.705 mmol scale) in pyridine (5 mL) under a nitrogen atmosphere. After the vigorous reaction has ceased, the mixture is heated at 98° C. for 22 hr. LC/MS indicates the reaction is incomplete and a further amount of acetyl chloride (50 μL) is added and the reaction mixture is heated for an additional 40 min. The reaction mixture is allowed to cool, then evaporated to dryness. The residue is suspended in water and extracted with three portions of ethyl acetate. The combined ethyl acetate layer is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to leave a sticky, orange residue. The residue is extracted with five portions of heptane and the combined extract is evaporated. The residue is purified by flash chromatography on a 10-gram silica gel cartridge by elution with heptane:dichloromethane (9:1, increasing to 4:1). Clean fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine (47 mg, 20% combined yield from Steps 3 and 4) as an off-white solid. MS: m/e=234 (M+H); 1H NMR (CDCl3, δ, ppm): 7.94 (1H, s), 4.00 (3H, s), 2.74 (3H, s), 2.64 (3H, s), 2.60 (2H, q), 1.10 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:28]([N:30](CC)CC)C>ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:30][CH3:28])=[O:15])=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2F)c(C(=O)O)cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-6-methylnicotinic acid (500 mg, 1.88 mmol) in dichloromethane (10 mL) at 0° C. was added oxalyl chloride (0.988 mL, 11.29 mmol) drop wise followed by DMF (0.2 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was taken in up dichloromethane (50 mL) and cooled to 0° C. Methylamine hydrochloride (1.27 g, 18.82 mmol) was added to followed by triethylamine (2.62 mL, 18.82 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N,6-dimethylnicotinamide (520 mg, 1.43 mmol, 76% crude yield) as yellow solid. The material was carried forward without further purification. LC/MS (ESI) m/e 279.0 [(M+H)+, calcd for C14H13ClFN2O 279.1]; LC/MS retention time ((Method I) tR=1.82 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)=[CH:33][CH:34]=2)=[O:39])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(=O)OC)cc3)cc2)cc1)C(=O)OCC
Yield: 37.8 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (375 mg), which is the product of Reference example 6, 4′-methoxycarbonylbiphenyl-4-carboxylic acid (328 mg) and carbonyldiimidazole (225 mg) and the reaction mixture was treated to afford the title compound (257 mg) as colorless crystals.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>CS(C)=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CS(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 ml 0.1M veronal-Na/HCl buffer, pH 8.3/50% (v/v) DMSO, containing 100 mM Boc-Phe-OCam, 300 mM H-Leu-NH2 and 100 μM trypsinogen is agitated at room temperature under pH control. After 3 hours, the reaction is stopped as described in Example 3. The yield is analytically determined with HPLC to be 93% of theory.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH2:8]([N+:12]#[C-:13])[CH2:9][CH2:10][CH3:11].[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>Cl(O)(=O)(=O)=O>[CH2:8]([NH:12][C:13]1[N:4]2[C:5]([S:6][C:2]([CH3:1])=[CH:3]2)=[N:7][C:22]=1[C:21]1[CH:24]=[CH:25][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: Cc1cnc(N)s1
Reactant: [C-]#[N+]CCCC
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCNc1c(-c2ccc(C(C)(C)C)cc2)nc2sc(C)cn12

Procedure:
Compound 42 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 5-methyl-thiazol-2-yl-amine solution (0.1 M, MC), 0.575 ml (0.115 mmol) n-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 4-tert-butylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w 20%) in a substance library.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[ClH:15].[N+:16]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O-:18])=[O:17].C(N(CC)CC)C.Cl>C(O)C>[ClH:15].[N+:16]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[O:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)=[O:4])[CH2:27][CH2:28]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(OC2CCNCC2)c1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CN1CCC(Oc2cccc([N+](=O)[O-])c2)CC1)c1ccc2ccccc2c1

Procedure:
0.63 g of 2-bromo-2'-acetonaphthone, 0.65 g of 4-(m-nitrophenoxy)piperidine hydrochloride, and 1 g of triethylamine were added to 100 ml of ethanol. The mixture was refluxed for 30 min. The solvent was distilled off, and dichloromethane was added to the residue. The mixture was washed with water and dried. The dichloromethane was distilled off, and the residue was purified by column chromatography (silica gel) to prepare an oleaginous intended compound. The compound was converted into a hydrochloride by an ordinary method and then recrystallized to prepare 0.15 g of an intended hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[NH:14][C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1.[CH3:24]I>C[O-].[Na+].CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:24])[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: CI
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,5,6,7-tetrahydro-2H-cyclopenta[d]pyrimidine-2,4(3H)dione in sodium methylate/methanol with methyl iodide there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,5,6,7-tetrahydro-1-methyl-2H-cyclopenta[d]-pyrimidine-2,4(3H)-dione, m.p. 125°-127° C.;
Reaction SMILES: C(O[C@H](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N[C:81](=O)[C@H:82]([O:84]CC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:81][CH2:82][OH:84])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CCO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]([CH2:25][CH2:26][NH:27][CH3:28])[CH2:19][CH2:20]CC(O)=O)[N:8]=2)=[CH:4][CH:3]=1.[OH-:31].[Na+].Cl.C([O:36][CH2:37]C)C>CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]([CH2:25][CH2:26][NH:27][CH3:28])[CH2:19][CH2:20][C:37]([OH:36])=[O:31])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CNCCC(CCCC(=O)O)n1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCCC(CCC(=O)O)n1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
15 g 4-(4-chlorobenzyl)-2-(5-methylamino-1-carboxymethyl-3-pentyl)1(2H)-phthalazinone (Example 2) are dissolved in 150 ml methanol and reacted with 21 ml 5M sodium hydroxide solution. The solution is heated for 1.5 hours to 50° C., then concentrated in a rotary evaporator, and the residue reacted is with 105 ml 1M HCl (pH 6). The aqueous solution is first shaken with diethylether to remove nonpolar impurities and then extracted with dichloromethane. The combined dichloromethane phases are concentrated, and the raw product is crystallized from ethanol. The crystalline product is precipitated absorptively with ether and dried in a vacuum (55° C./2 Torr).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[F:3][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To 3.96 g (99 mmol) of hexanes washed 60% sodium hydride in 150 ml of N,N-dimethylformamide was added portionwise as a solid 15 g (90 mmol) of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one. When the addition was complete the reaction was stirred at room temperature for 10 min, after which time 19.8 g (108 mmol) of isobutyl iodide was added. The reaction was then stirred overnight before quenching onto 200 ml of water. The aqueous phase was extracted with EtOAc (2×150 ml) and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to give the desired alkylated product, as a yellow oil (13 g, 65% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC1CCCCC1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3-Cyclohexyl-1-propanol (5.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (10.2 g) and N-bromosuccinimide (6.90 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (7.17 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=O)OCC)C.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.O>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:24][CH:23]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
2.63 g of sodium hydride are added to 50 ml of dimethylformamide. The mixture is cooled to 0° C. and 16 g (58.6 mmol) of (4-nitro-benzyl)-phosphonic acid diethyl ester is added portionwise. The solution is stirred at room temperature for 1.5 h, then cooled to −10°. A solution of 6.09 g (50 mmol)4-fluoro-benzaldehyde in 10 ml dimethylformamide is slowly added to the mixture at −10°. Stirring at room temperature for 45 min followed by additon of 250 ml water yields a precipitate which is filtered and recrystallised from ethanol/water 85:15 to yield 10.81 g (91%) of a yellow solid. MS: m/e=243.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7](Cl)[C:8]3[N:9]2[C:12]([O:15][CH3:16])=[N:13][N:14]=3)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:26][CH:23]([CH3:25])[CH3:24])[C:8]3[N:9]2[C:12]([O:15][CH3:16])=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: COc1nnc2c(Cl)nc3ccc(Br)cc3n12
Reactant: CC(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nnc2c(NC(C)C)nc3ccc(Br)cc3n12
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 8-bromo-4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline (2.0 g) in DMF (50 mL) was added solid sodium bicarbonate (1.1 g) and isopropylamine (0.82 mL). The resulting mixture was stirred at 23° C. for 18 hrs. and then diluted with EtOAc. The mixture was washed sequentially with water and brine, and then dried over sodium sulfate. Concentration afforded (8-bromo-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-isopropyl-amine as a light yellow solid. MS (M+H)+=337.3.
Reaction SMILES: S(OC)(OC)(=O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O.C([O-])([O-])=O.[K+].[K+].[ClH:20].[CH:21]1([CH:24]([NH2:28])[CH:25]2[CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[ClH:20].[CH:21]1([CH:24]([CH:25]2[CH2:27][CH2:26]2)[NH:28][C:9]2[CH2:10][CH2:11][CH2:12][N:8]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCCN1
Reactant: NC(C1CC1)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: C1CN=C(NC(C2CC2)C2CC2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 0.2 mol (25.2 g) of dimethyl sulphate and 0.2 mol (17 g) of 2-pyrrolidinone is heated at 60° C. overnight. The reaction mixture is poured into a saturated iced K2CO3 solution. The aqueous phase is extracted twice with ether, and the combined organic phases are dried and concentrated. The residue is then distilled under reduced pressure. 2 mrnmol of the resulting product are dissolved in 20 ml of methanol, and 2 mmol (295 mg) of dicyclopropylmethylamine hydrochloride are added. The reaction mixture is stirred at 50° C. for 2 hours. After evaporation of the methanol, the residue is taken up in water, rendered alkaline and extracted twice with ether. The organic phase is dried, concentrated and purified to yield the expected product. The corresponding, hydrochloride is obtained by the action of a titrated solution of hydrochloric acid in ethanol.
Reaction SMILES: O1C2C=CC=CC=2C=C1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:11]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CN(C)[CH:34]=[O:35]>>[O:35]1[C:34]2[CH:19]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[C:17]1[CH:27]1[CH2:26][CH2:25][CH2:24][O:23][CH:22]1[N:12]1[C:13]2[C:18](=[CH:17][C:16]([C:19]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:21])=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CC(C)N
Reactant: CN(C)C=O
Product: CC(C)NC(=O)c1ccc2c(cnn2C2OCCCC2c2cc3ccccc3o2)c1
Reaction time: 48 h
Yield: 81 %

Procedure:
To solution of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (190 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboimide hydrochloride (109.3 mg, 0.57 mmol) in dimethylformamide was added isopropylamine (48 μL, 0.57 mmol) and the mixture allowed to stir under a nitrogen atmosphere for two days. An additional 2 equivalents of isopropylamine was added to the reaction and allowed to stir for another day. Solvent was removed and the reaction was extracted with ethyl acetate. The crude material was purified by preparative HPLC to yield the title compound (209 mg, 81% yield). ES-MS (m/z) 404 [M+1]+.