Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.ClC1(C(O)=O)N(C2C(Cl)=CC=CN=2)NC=C1.[Cl:22][C:23]1[CH:27]=[C:26]([C:28]([OH:30])=O)[N:25]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[N:24]=1.N1C=CC=CC=1.[NH2:44][C:45]1[C:53]([CH3:54])=[CH:52][C:51]([Cl:55])=[CH:50][C:46]=1[C:47](O)=[O:48]>C(#N)C.O>[Cl:55][C:51]1[CH:52]=[C:53]([CH3:54])[C:45]2[N:44]=[C:28]([C:26]3[N:25]([C:31]4[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=4)[N:24]=[C:23]([Cl:22])[CH:27]=3)[O:30][C:47](=[O:48])[C:46]=2[CH:50]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C1(Cl)C=CNN1c1ncccc1Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g 13 mmol) was dissolved in acetonitrile (10 mL) and the mixture was cooled to −5° C. A solution of 5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 8, Step D) (2.58 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 6, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to 0° C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (15 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile 2×5 mL), and dried under nitrogen to afford the title product as a pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201° C. HPLC or the product using a Zorbax® RX-C8 chromatography column (4.5 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>O.CO.C(Cl)Cl>[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc2ccc(C(C)=O)cc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2ccc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of KOH 70 mg, 10 mmol) in water (3.5 mL) was added dropwise to a cooled solution of the ester 168 (640 mg, 2.81 mmol) in MeOH (10 mL) and CH2Cl2 (10 mL) at 0° C. After allowing the mixture to warm to room temperature and stirring for 96 h, excess CH2Cl2 and water were added. The aqueous portion was acidified (pH 2) with 2N HCl and the resulting white precipitate was extracted with EtOAc (×2). The combined EtOAc extracts were washed with water, brine, and dried, to give 7-acetyl-2-naphthoic acid (169). (575 mg, 96%) as a colorless solid. A sample was recrystallised from petroleum ether/CH2Cl2/Et2O: mp 224-228° C.; 1H NMR: (CDCl3) 8 (CO2H not observed) 8.82 (s, 1H), 8.60 (s, 1H), 8.23 (dd, J=8.6, 1.6 Hz, 1H), 8.18 (dd, J=8.7, 1.7 Hz, 1H), 7.97 (c, J=8.7 Hz, 2H), 2.76 (s, 3H). Anal. (C13H10O3) C, H.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([NH:29]C(OC)=O)([CH3:28])[CH2:26][OH:27])=[C:18]([Cl:34])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O1CCCC1.CO>O>[NH2:29][C:25]([CH3:28])([CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:17][C:18]=1[Cl:34])[CH2:26][OH:27]
Reactant: COC(=O)NC(C)(CO)CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(N)(CO)CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Reaction time: 96 h
Yield: 66.8 %

Procedure:
The compound of Example 206 (527 mg) was dissolved in a mixed solvent composed of a 5 mol/L aqueous solution of potassium hydroxide (2 mL), tetrahydrofuran (2 mL) and methanol (3 mL). This mixture was refluxed and stirred for 4 days. Subsequently, the reaction mixture was diluted with water and was extracted with ethyl acetate. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, was dried over anhydrous magnesium sulfate, and was then concentrated. The resulting residue was purified on a silica gel column chromatography (aminated silica gel, ethyl acetate:ethanol=20:1) to give the desired product as a pale yellow oil (311 mg).
Reaction SMILES: C(OC(N1C2[C:11](=[CH:12][C:13]([C:17](C)([CH3:24])[O:18][SiH2]C(C)(C)C)=CC=2)C=C1)=O)(C)(C)C.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1[CH:38]=[CH:37][N:36]=[CH:35]1>CN(C)C=O>[C:29]([Si:26]([CH3:28])([CH3:27])[O:18][C:17]1[CH:13]=[C:12]2[C:37](=[CH:38][CH:24]=1)[NH:36][CH:35]=[CH:11]2)([CH3:32])([CH3:31])[CH3:30]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1

Procedure:
A solution of 5-hydroxyindole (1-3, 5.50 g, 41.3 mmol, 1 equiv), tert-butyldimethylsilyl chloride (7.47 g, 49.6 mmol, 1.20 equiv), and imidazole (7.03 g, 103 mmol, 2.50 equiv) in N, N-dimethylformamide (20 mL) was stirred at 23° C. for 20 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water (3×), then dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (40% dichloromethane in hexanes, then 60% dichloromethane in hexanes) to give 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole as a colorless oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.00 (br s, 1H), 7.22 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=2.8 Hz), 7.06 (d, 1H, J=2.3 Hz), 6.76 (dd, 1H, J=8.6, 2.3 Hz), 6.44 (m, 1H), 1.00 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:40]([O:47][C:48](=[O:65])[C@H:49]([CH3:64])[NH:50][C:51](=[O:63])[C@H:52]([CH3:62])[N:53]([C:55](=[O:61])[C@H:56]([CH:58]([CH3:60])[CH3:59])[NH2:57])[CH3:54])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH2:40]([O:47][C:48](=[O:65])[C@H:49]([CH3:64])[NH:50][C:51](=[O:63])[C@H:52]([CH3:62])[N:53]([C:55](=[O:61])[C@H:56]([CH:58]([CH3:60])[CH3:59])[NH:57][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:17])[CH3:54])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 13.17 g (0.0537 mole) of Boc-N-methyl-L-leucine in 370 ml of dry dichloromethane was stirred and cooled at 0° C. as one-half of 13.15 g. (0.130 mole) of dry triethylamine was added, followed by 15.05 g (0.0591 mole) of BOP-Cl. This was stirred at 0° C. for 3 hours. The remainder of the triethylamine was added, followed by a solution of 13 g (0.0358 mole) of L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 50 ml of dry dichloromethane. The reaction was stirred at ice temperature for 22 hours, then washed with 125 ml of a 10% solution of potassium bisulfate. The organic layer was further washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated to a small volume, and chromatographed on silica gel eluting with 1:1 ether/hexane gradually increasing the ether to 2:1. The product weighed 15.8 g (75% of theory), and the FAB m.s. showed a molecular ion peak at 591.
Reaction SMILES: [Na].CC1C=CC=CC=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2(C#N)[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(O)C>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:25][CH2:24][C:19]3([O:20][CH2:21][CH2:22][O:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
To a stirred and hot (±100° C.) mixture of 101 parts of sodium and 450 parts of methylbenzene is added dropwise a solution of 189 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile in 450 parts of methylbenzene and 100 parts of absolute ethanol (temperature remained at about 90° C.). Then there are added successively and dropwise 260 parts of absolute ethanol and 160 parts of methanol. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto ice-water and the product is extracted with trichloromethane. The extract is washed successively with a hydrochloric acid solution 5%, a sodium bicarbonate solution 5% and with water, dried, filtered and evaporated, yielding 167 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane; mp. <60° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (700 mg, 2.48 mmol), 4-cyanobenzohydrazide (439 mg, 2.73 mmol) and anhydrous THF (20 mL) were placed in a 50 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (335 mg, 2.48 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (589 mg, 3.07 mmol) at −15° C. followed by triethylamine (0.43 mL, 3.07 mmol). The reaction mixture was maintained −15° C. and stirred for 1 h, after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (30 mL). The THF solution was concentrated to ca. 10 mL, whereupon EtOAc (200 mL) was added followed by extraction with 5% citric acid (3×100 mL). The phases were partitioned and the organic phase washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to furnish a light yellow solid (920 mg, 87% yield). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.80 (br s, 2H), 8.09 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 5.65 (d, J=6.7 Hz, 1H), 4.76 (br s, 1H), 4.43-4.35 (m, 1H), 4.15 (dd, J=3.7 Hz, 6.7 Hz, 1H), 2.94-2.79 (m, 2H) 1.38 (d, J=6.8 Hz, 3H) and 1.18 (t, J=7.6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]=[CH:11][N:10]=1)([O-])=O.C(O)(=O)C.O>[Fe].C(O)C>[ClH:19].[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1N
Product: Cl
Yield: 215.9 %

Procedure:
1 g of powdered iron was added in portions to a mixture comprising 1 g of 4-(3-nitro-4-methoxybenzyl)amino-6-chloroquinazoline, 4 ml of acetic acid, 4 ml of water and 40 ml of ethanol, while heating the mixture under mild reflux. The obtained mixture was heated under reflux for 2 hours and filtered to remove insolubles. Concentrated hydrochloric acid was added in portions to the brown filtrate obtained above to give a yellow transparent solution. This solution was cooled with ice to precipitate crystals. The crystals were recovered by filtration and dried to give 1.1 g of 4-(3-amino-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride. This hydrochloride was dissolved in ethanol/water and the obtained solution was made alkaline by adding a 15% aqueous solution of sodium hydroxide in portions. Water was added to the resulting alkaline solution in portions to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 770 mg of 4-(3-amino-4-methoxybenzyl)amine-6-chloroquinazoline (an aniline derivative), Separately. 1 ml of formic acid was dropped into 2 ml of acetic anhydride under cooling with ice and the obtained mixture was heated at 50° C. for 15 minutes and immediately cooled with ice, followed by the addition of the above aniline derivative as such (in a crystalline state), The obtained mixture was reacted at that temperature for one hour and at room temperature for one hour, followed by the addition of water. The crystals thus formed were recovered by filtration, washed with water and dried to give 130 mg of the title compound.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][NH:20]3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:45][C:46]1[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49].CN1CCOCC1>CN(C=O)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[C:48](=[O:49])[C:47]3[CH:51]=[CH:52][CH:53]=[C:54]([CH3:55])[C:46]=3[CH3:45])=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:29][CH:30]=1)#[N:3]
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2Cc3ccccc3C[C@H]2C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)c1C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-Tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide hydrochloride (Example 1, Step C) (0.23 g, 0.52 mmol) in DMF (5 mL) was added l-hydroxybenzotriazole (0.079 g, 0.52 mmol), EDC (0.099 g, 0.52 mmol), 2,3-dimethylbenzoic acid (0.077 g, 0.52 mmol) and N-methylmorpholine (0.23 mL, 2.08 mmol). After stiffing for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned betweem EtOAc (50 mL) and saturated NaHCO3 solution (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and concentration gave the title compound after purification by preparative HPLC on a Delta-pak C-18 column eluting with 0.1%TFA/H2O: 0.1%TFA/CH4CN, 95:5 to 5:95.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:5]=3[C:4]=2[N:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:24]([NH2:28])=[N:25][NH:26][CH:27]=1)=[O:22])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[CH2:18]([O:20][C:21]([C:23]1[C:24]([NH2:28])=[N:25][N:26]([C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:5]=4[C:4]=3[N:3]=2)[CH:27]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ncc3c(n2)-c2ccc(OC)cc2CC3)nc1N
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 54.1 %

Procedure:
A mixture of 2-Chloro-8-methoxy-5,6-dihydro-benzo[h]quinazoline (2, 5.0 g, 20.27 mM), 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (3.14 g, 20.27 mM), Cs2CO3 (8.59 g, 26.35 mM) in DMF (40 ml) was stirred at 100° C. for 2.5 hr then cooled to room temperature and diluted with water (400 ml). The resulting precipitate was isolated via filtration and the solid washed with water (3×50 mL) then methanol (3×30 ml). The solid was dried under reduced pressure which was comprised of a 7:3 mixture of 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester(3) and it's isomer 5-Amino-1-(5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester identical to the material prepared in preparation 6 below. The solid was then crystallized from dichloromethane (40 ml) to give the slower (TLC, EtOAc) of two isomers 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (3, 4.0 g, 2 crops, 54% yield). ES-MS MH+ 366. The mother liquors may be purified via chromatography on silica eluting with ethyl acetate to provide the faster isomer 5-Amino-1-(5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2](=[C:12]([Cl:14])[Cl:13])[C:3](=[O:11])CCC(OCC)=O.[CH:15]([O-:20])([O-])[O:16][CH2:17][CH3:18].[C:21]([O:24][C:25](=O)[CH3:26])(=O)[CH3:22]>>[Cl:1][C:2](=[C:12]([Cl:14])[Cl:13])[C:3](=[O:11])[C:22](=[CH:21][O:24][CH2:25][CH3:26])[C:15]([O:16][CH2:17][CH3:18])=[O:20]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CCC(=O)C(Cl)=C(Cl)Cl
Reactant: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(Cl)=C(Cl)Cl

Procedure:
305 g (1.24 mol) of ethyl 4,5,5-trichloro-3-oxo-4-pentenecarboxylate are heated with 275 g (1.86 mol) of ethyl orthoformate and 316.0 g of acetic anhydride at 150°-160° C. for three hours. All volatile components are removed initially in vacuo, then under a high vacuum up to 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:44][Mg]Br>C1COCC1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[CH3:44])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 97.4 %

Procedure:
5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (877.5 mg, 1.519 mmol) was suspended in THF (15 mL) and methylmagnesium bromide (3.0 M in diethyl ether, 1.5 mL, 4.5 mmol) was added. More THF (2.5 mL) was added after about 10 min. After 40 additional min, the reaction was quenched with saturated ammonium chloride and diluted with water (20 mL). The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to 40:1 DCM/MeOH) to afford 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (878.2 mg). 1H NMR (CDCl3, 400 MHz) δ 11.62 (s, 1H), 8.82 (d, J=2.54 Hz, 1H), 8.30 (d, J=2.54 Hz, 1H), 8.26 (d, J=2.74 Hz, 1H), 7.88 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.21 (dd, J=12.91 Hz, 8.61 Hz, 4H), 6.90-6.82 (m, 4H), 6.71 (d, J=8.80 Hz, 1H), 4.93-4.86 (m, 3H), 4.82 (d, J=6.26 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.58 (s, 3H), 1.72 (d, J=3.91 Hz, 1H), 1.52 (d, J=6.46 Hz, 3H). m/z (ESI, +ve ion) 594 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[C:6]([CH3:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1>[Pt].C(O)C>[CH3:18][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)[NH2:19]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1cccc(C(C)C)c1
Agent: [Pt]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1cccc(C(C)C)c1

Procedure:
3,5-Dimethyl-4-(3'-isopropylphenoxy)-nitrobenzene (5.21 g) and 521 mg of 10% platinum on carbon in 150 ml ethanol are reduced under hydrogen on a Parr shaker. The solution is filtered through Celite to remove catalyst and the filtrate is stripped to give 3,5-dimethyl-4-(3'-isopropylphenoxy)-aniline which is then fused with 50 g of dimethyl oxalate at 120° for four hours. The resulting mixture is concentrated under high vacuum and the residue chromatographed on silica gel with 9:1 toluene:ethyl acetate as eluent to yield methyl N-[3,5-dimethyl-4-(3'-isopropylphenoxy)-phenyl]oxamate; NMR (CDCl3): δ1.2 (6H, d), 2.1 (6H, s), 2.8 (1H, m), 4.0 (3H, s), 6.5 (1H, d of d), 6.7 (1H, t), 6.9 (1H, d of d), 7.2 (1H, t), 7.4 (2H, s), 8.8 (1h, br s).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].Cl.[H-].[Na+].Cl[C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:28])=[CH:25][C:24]=2[O:39][CH3:40])[N:13]=1>O1CCOCC1.O>[NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:16]1[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:12][N:13]=[C:14]([NH:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)=[O:28])=[CH:25][C:24]=2[O:39][CH3:40])[N:15]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(O[C@@H]2CCC[C@H]2N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R,R)-2-aminocyclopentanol×HCl (155 mg) is added to a suspension of NaH (135.2 mg) in dioxane (0.75 mL) and stirred for 30 min at RT. Then 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (250 mg) is added. After 18 h, H2O (50 mL) is added. The precipitate formed is filtered off, washed with H2O, dissolved in CH2Cl2 and extracted with aqueous KHSO4 solution (10%). The aqueous phase is made basic again with K2CO3 and extracted with CH2Cl2. The organic phase is dried on magnesium sulphate, filtered to remove the desiccant and the solvent is eliminated in vacuo.