Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][NH:25][C:24]1=[O:28]>CN1CCCC1=O>[Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:6][CH:7]=1
Reactant: NCCN1CCNC1=O
Reactant: Clc1ncc(Br)c(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1NCCN1CCNc1ncc(Br)c(-c2cccs2)n1
Temperature: 110 °C

Procedure:
5-Bromo-2-chloro-4-(thiophen-2-yl)pyrimidine (2.0 g, 7.25 mmol) dissolved in N-methyl pyrrolidone (25 mL) was treated with potassium carbonate (2 g, 14.5 mmol) and 1-(2-aminoethyl)imidazolidin-2-one (1.125 g, 8.71 mmol). The reaction was heated to 110° C. overnight. The reaction was poured into ice water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine and then dried with sodium sulfate. Purification was achieved by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=2 g. MS (M+H)+ 368/370.
Reaction SMILES: [N:1]1([CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(C2C=CC=CC=2)=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=N1.[CH:25]([NH2:27])=O>>[C:19]1([C:10]2[N:27]=[C:25]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:1]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(c1ccccc1)C(c1ccccc1)n1nnc2ccccc21
Reactant: NC=O
Product: c1ccc(-c2nc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 50 %

Procedure:
The conversion of benzotriazene derivatives into 4-phenyl quinazolines, such as the transformation of 1,2-diaryl-2-(benzotriazol-1-yl)enamines prepared from lithiated (α-arylbenzotriazol-1-yl)methane and nitriles to afford 2,4-arylquinazolines, and the reaction between 2-(benzotriazol-1-yl)-1,2-diphenylethanone and formamide at 150° C. to afford 50% of 2,4-diphenylquinazoline [41]; and
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(F)cc1OCCc1cccc2ccccc12
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Yield: 81 %

Procedure:
A solution of S)-3-[4-fluoro-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonyl amino]-N-methoxy-N methyl-succinamic acid tert-butyl ester (1.10 g, 2.0 mmol) in pyrollidine (10 mL) was heated at 50° C. for 5 h. The reaction mixture was allowed to cool and then was added EtOAc (150 mL). The resulting solution was washed sequentially with the following solutions: 5% citric acid, saturated NaHCO3, and brine. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using flash silica gel chromatography (25% EtOAc in hexanes). (S)-N-Methoxy-N-methyl-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonyl amino]-succinamic acid tert-butyl ester was obtained in 81% yield (1.0 g) as a off white foam. MS (APCI) m/z 610.3 (M−1).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13](=[O:39])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]([CH:37]=[O:38])[CH:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])O)[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:12][C:13](=[O:39])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([CH:37]=[O:38])=[CH:22][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][C:25]=2[Cl:36])[CH2:17][CH2:16]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc2ncc(Cl)c(C(O)C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2ncc(Cl)c(C=C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Acetic anhydride (9.95 g, 97.5 mmol, 10.0 eq) is added at room temperature to a stirred solution of {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-2-hydroxy-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (4.5 g, 9.7 mmol, 1.0 eq) in anhydrous pyridine (100 mL). After 30 hours stirring at room temperature and 90 hours stirring at 50° C., solvent is removed and the residue is extracted with ethyl acetate (3×100 mL) and a saturated sodium hydrogen carbonate aqueous solution (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:dichloromethane, 9:2:1 to 6:2:1, v/v/v) to afford {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (3.40 g, 79% yield).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=1.CI>O>[Br:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][O:16][CH3:3])[CH:10]=1
Reactant: OCc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1cncc(Br)c1
Reaction time: 1 h

Procedure:
Sodium hydride (61% in oil) (11 mg) was added to a DMF (0.9 ml) solution containing (5-bromopyridin-3-yl)methanol (34 mg) under ice cooling, followed by stirring for 1 hour. Then, methyl iodide (17 μl) was added, followed by stirring at room temperature for 13 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and a light yellow solid of 3-bromo-5-(methoxymethyl)pyridine (26.5 mg) was thus obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:15][C:16]([C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CC(=O)CC>[CH2:28]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:22]([CH:26]=1)[C:23]([NH2:25])=[O:24])=[O:17])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: CCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCOc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O
Yield: 99.8 %

Procedure:
A mixture of potassium carbonate (3.73 g), 5-(N,N-dibenzylglycyl) salicylamide (10 g) and 1-iodo heptane (7.5 g) in butanone (200 ml) was stirred and heated under reflux for 24 hours. The solid was filtered off and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The dried (MgSO4) ethyl acetate solution was evaporated to give a yellow oil (12.6 g) which crystallised twice from isopropanol to yield the ether (6.3 g) m.p. 97.5°-98°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:5][N:6]=[N+:7]=[N-:8].[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:23][C:22]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[C:10]([Cl:21])[CH:9]=2)[N:7]=[N:8][C:24]=1[C:25]([NH2:27])=[O:26]
Reactant: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reactant: N#CCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N

Procedure:
3,5-dichloro-4-(4′-chlorobenzoyl)benzyl azide (858.D) (1 mole) is reacted with cyanoacetamide (1.69 mole) in hot Acetonitrile, and Potassium carbonate, (6.2 mole) to give 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide (858.E).
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=O.B.C1COCC1.CO>C1COCC1>[C:13]1([C@@H:2]([NH2:1])[CH2:3][NH:4][CH2:5][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](CNC(=O)C1CCOCC1)c1ccccc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CNCC1CCOCC1)c1ccccc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
(R)-tetrahydro-pyran-4-carboxylic acid (2-amino-2-phenyl-ethyl)-amide (450 mg, 1.82 mmol) was dissolved in dry THF; and 5.45 ml of borane-THF complex (1M in THF, 5.45 mmol) was added. The solution was refluxed for 3 hours. The reaction was then cooled to room temperature. Methanol (7 ml) was added slowly through the condenser, and the reaction brought to reflux for a further 15 minutes. The reaction was again cooled to room temperature; and the volatiles were removed under high vacuum. More methanol was added and subsequently evaporated (3×15 ml). The resulting residue was dissolved in ethylenediamine (7 ml) and the solution was heated to 60° C. for 20 minutes. The reaction was then quenched with the addition of a saturated aqueous solution of NaHCO3. This aqueous phase was extracted with DCM; and the organic extracts dried over Na2SO4. The solvent was removed in vacuo to give the crude product. Purification by flash chromatography over silica gel afforded (R)-1-Phenyl-N2-(tetrahydro-pyran-4-ylmethyl)-ethane-1,2-diamine (304 mg, 72%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
Bromine (0.715 ml) was added dropwise to tert-butyl 4-(3-methoxyphenyl)piperazine-1-carboxylate (3.4 g) dissolved in cold acetic acid (25 ml) under argon. The resulting solution was stirred at room temperature for 90 minutes. The reaction mixture was concentrated to dryness and diluted with ethyl acetate, dichloromethane and a saturated aqueous solution of sodium bicarbonate. The phases were stirred, separated and the organic phase was dried over magnesium sulfate and concentrated in the presence of silica gel. The crude product was purified by flash chromatography on silica gel eluting with 10 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-methoxy-phenyl)piperazine-1-carboxylate (1.770 g, 41.0%). NMR Spectrum: (CDCl3) 1.48 (s, 9H), 3.08-3.17 (m, 4H), 3.54-3.62 (m, 4H), 3.88 (s, 3H), 6.40 (dd, 1H), 6.47 (d, 1H), 7.37 (d, 1H)
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([CH2:38][NH:39][C:40]([NH:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:41])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:51][O:52]C(=O)C)(=O)C.N>CO>[NH3:14].[OH:10][C@@H:9]1[C@H:5]([OH:4])[C@@H:6]([CH2:51][OH:52])[O:7][C@H:8]1[N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([CH2:38][NH:39][C:40]([NH:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:41])=[N:18][C:19]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 3 h
Yield: 109.8 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)tetrahydro-3-furanyl acetate (100 mg, 0.13mmol) (Preparation 6) in methanol (50 ml) was saturated with ammonia gas and then left to stand for 3 hours. The solvent was removed under reduced pressure to give a residue that was purified by elution through a plug of silica gel with dichloromethane: methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound as a foam (45 mg).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([SH:20])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.[C:22](=O)([O-])[O-].[K+].[K+].CI.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([S:20][CH3:22])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
A mixture of 3.43 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 20 ml of absolute acetonitrile and 1.38 g of (10 mmol) of potassium carbonate is treated with 0.93 ml (15 mmol) of methyl iodide and the mixture is stirred at 40° C. for 5 hours. The reaction mixture is then treated with saturated, aqueous sodium carbonate solution and extracted repeatedly using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.4 g (95% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methylthio-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of oil.
Reaction SMILES: Br[C:2]1C=C2C(=C[CH:11]=1)NC(=O)CC2C(NC[C@@H](C(O)=O)NC(=O)C1C=CC(C(NCC2C=CC=C(O)C=2)=O)=CC=1Cl)=O.[Cl:42][C:43]1[CH:68]=[C:67]([C:69]([NH:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([OH:79])[CH:74]=2)=[O:70])[CH:66]=[CH:65][C:44]=1[C:45]([NH:47][C@H:48]([C:62]([OH:64])=[O:63])[CH2:49][NH:50][C:51]([C:53]1O[C:55]2[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=2[CH:57]=1)=[O:52])=[O:46]>>[Cl:42][C:43]1[CH:68]=[C:67]([C:69]([NH:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([OH:79])[CH:74]=2)=[O:70])[CH:66]=[CH:65][C:44]=1[C:45]([NH:47][C@H:48]([C:62]([OH:64])=[O:63])[CH2:49][NH:50][C:51]([CH:53]1[CH2:11][CH2:2][C:55]2[C:56](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:57]1)=[O:52])=[O:46]
Reactant: O=C1CC(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)c2cc(Br)ccc2N1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc3ccccc3o2)C(=O)O)c(Cl)c1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)C2CCc3ccccc3C2)C(=O)O)c(Cl)c1

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(DL-7-methoxy-1,2,3,4,4αβ,9,10,10αβ-octahydro-2β-phenanthrenecarbonyl)]amino-L-alanine; 3-(6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(benzofuran-2-carbonyl)amino-L-alanine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])N)[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16]([C@@H:17]1[CH2:19][S:20][C:5]([C:4]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])=[N:6]1)=[O:21])[CH3:14]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: COc1ccc(C#N)c(OC)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CSC(c2ccc(OC)cc2OC)=N1

Procedure:
2,4-Dimethoxybenzonitrile, (R)-cysteine ethyl ester and about 5 equivalents of triethylamine are refluxed in ethanol for about 6-8 hours to obtain ethyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14]C)=[O:13])[CH:8]=2)[N:3]=1.C1C[O:19]CC1>>[O:19]=[C:2]1[CH:11]=[CH:10][CH:9]2[CH:4]([CH:5]=[CH:6][C:7]([C:12]([OH:14])=[O:13])=[CH:8]2)[NH:3]1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2nc(Cl)ccc2c1
Product: O=C1C=CC2C=C(C(=O)O)C=CC2N1

Procedure:
A solution of methyl 2-chloroquinoline-6-carboxylate (60 mg, 0.271 mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to 60° C. in a heating block. LCMS shows major product 86% peak area corresponding to title compound with hydrolysis of methyl ester (m/z=189.9). The reaction was concentrated and used in the subsequent amide coupling steps without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C[Al](C)C.[CH2:28]([N:30]([C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][N:44]=2)[S:39][C:38]=1[C:46]([O-])=[O:47])C(=O)C(F)(F)F)[CH3:29]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([NH:2][C:46]([C:38]2[S:39][C:40]3=[N:41][CH:42]=[CH:43][N:44]=[C:45]3[C:37]=2[NH:30][CH2:28][CH3:29])=[O:47])[CH:4]=1)=[O:23])([CH3:20])[CH3:19])#[N:22]
Reactant: CCN(C(=O)C(F)(F)F)c1c(C(=O)[O-])sc2nccnc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCNc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Temperature: 25 °C
Yield: 5 %

Procedure:
To a suspension of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (40 mg, 0.121 mmol) in toluene (1 mL) was added trimethylaluminum (0.243 mL, 0.485 mmol) and stirred for 15 at rt. 7-(N-ethyl-2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 45 (42.1 mg, 0.121 mmol) in toluene (1 mL) was added and the reaction was stirred overnight at 70° C. Diluted with EtOAc and washed with seignette salt solution. Organic layer was washed with brine, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(ethylamino)thieno[2,3-b]pyrazine-6-carboxamide 46 (3 mg, 4.96%). NMR (400 MHz, DMSO-d6) 1.20 (t, J=7.4 Hz, 3H), 1.75 (s, 6H), 2.22 (s, 1H), 3.98 (q, J=14.0 and 6.5 Hz, 12H), 7.26 (d, J=8.2 Hz, 1H), 7.58-7.64 (m, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.04-8.11 (m, 2H), 8.74 (d, J=2.3 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 9.53 (s, 1H), 10.32 (s, 1H). (m/z)=499 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:24](=[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=[CH:27][CH:28]=3)[C:23](Cl)=[N:22][N:21]=2)[CH:17]=[CH:16][N:15]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[CH2:1]([NH:8][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:19]=2)=[N:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Oc1cc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)ccn1
Solvent: ClCCl
Product: CC(C)(C)Oc1cc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)ccn1
Temperature: 100 °C
Yield: 50.8 %

Procedure:
Benzylamine (5.00 mL, 45.8 mmol) was added to 1-(2-(tert-butoxy)pyridin-4-yl)-4-chloro-5-phenylphthalazine (0.200 g, 0.513 mmol) and heated in a sealed tube at 100° C. for 12 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (50 mL) followed by brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using Combiflash Isco (REDISEP®, basic Al2O3, 80 g, 0-70% ethyl acetate/petroleum ether) to remove excess benzyl amine. The resulting residue was then purified by preparative HPLC (Condition 33 as described in general methods) to afford N-benzyl-4-(2-(tert-butoxy)pyridin-4-yl)-8-phenylphthalazin-1-amine (0.120 g, 50.8%) as a white solid. LCMS (Condition 34): retention time 2.67 min, [M+1]=461.2. HPLC (Condition 35): retention time=21.80 min, purity 99.30%. 1H NMR (400 MHz, DMSO-d6) δ 1.63 (s, 9 H), 4.50 (d, J=5.2 Hz, 2 H), 5.07 (t, J=5.2 Hz, 1 H), 6.90 (dd, J=0.4 Hz, J=0.8 Hz, 1 H), 7.00-7.03 (m, 2 H), 7.17 (dd, J=1.6 Hz, J=5.2 Hz, 1 H), 7.22-7.28 (m, 3 H), 7.42-7.50 (m, 5 H), 7.67 (dd, J=1.2 Hz, J=6.8 Hz, 1 H), 7.85-7.93 (m, 2 H), 8.31 (dd, J=0.4 Hz, J=5.2 Hz, 1 H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:9]([O-])=[O:10].[Na+].Cl.O>C(OCC)C>[OH:10][N:9]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(=NO)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 46.45 g (0.4 mol) of methyl acetoacetate in 200 ml of diethylether, 30.4 g (0.44 mol) of sodium nitrite was added and the mixture was cooled in an ice bath and treated dropwise with 40 ml (0.48 mol) of a concentrated hydrochloric acid. After stirring for 1 hour at room temperature, 200 ml of water was added and the mixture was extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off to obtain 50.09 g (yield: 86%) of a crude methyl 2-hydroxyiminoacetoacetate as a pale yellow oil. (2) Synthesis of methyl 2-benzyloxyiminoacetoacetate
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[C:14]([O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:18])[C:15]([CH3:17])=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C(O)=CC=C(O)C=1>C(O)C>[OH:23][CH:21]([CH2:20][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[CH2:22][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: CC1CC(C)(C)NC2CCCCC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
In a 500 ml 3-neck flask were placed 0.62 mole of 2,2,4-trimethyldecahydroquinoline (hereinafter referred to as TDQ), 0.62 mole of glycidyl methacrylate, 0.5 gram p-toluene sulfonic acid, 0.5 gram p-hydroquinone, and 5 mls of ethanol. The above mixture was heated and allowed to react overnight. The maximum pot temperature was approximately 188° C.