Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:29])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18])(=[O:11])=[O:10].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:7][N:8]([CH3:29])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([NH:36][C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1)=[O:18])(=[O:10])=[O:11]
Reactant: Nc1cccnc1
Reactant: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.06 ml, 0.69 mmol) in dichloromethane (5 ml) was added dropwise over 1 minute to a stirred solution of 5-[(dimethylamino)sulfonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 63; 230 mg, 0.69 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated under reduced pressure to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (64.5 mg, 0.69 mmol) and diisopropylethylamine (0.12 ml, 0.69 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times and saturated brine (10 mL) two times, dried over sodium sulfate, and evaporated in vacuo to give the crude product as a orange oil. The product was crystallized from methanol to yield the title compound as a white solid. 170 mg.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([C:26]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:11]=1>>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([C:26]([O:28][CH:29]4[CH2:34][CH2:33][N:32]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:31][CH2:30]4)=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:11]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N1CCC(OC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from isopropyl chloroformate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=538.3.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[OH:39][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 90% purity by HPLC. MS(ESI+): m/z=488.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)=[O:7])([CH3:4])[CH3:3].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)[CH:26]=[C:25]1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:1][C:2]([O:5][C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:25]2[N:24]([CH3:23])[C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH:14]=1)=[O:7])([CH3:4])[CH3:3]
Reactant: Cn1c(B(O)O)cc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A flask is charged with 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-bromo-pyridine (1.12 g, 3.0 mmol), N-methyl-6-chloroindole-2-boronic acid (754 mg, 3.6 mmol), finely crushed potassium phosphate (1.27 g, 6.0 mmol) and DMF (20 mL). After degassing for 15 min, Pd(PPh3)4 (173 mg, 0.15 mmol) is added. The flask is flushed with nitrogen and the mixture is heated to 90° C. and stirred for 5 h. The mixture is then cooled to room temperature and poured into water (100 mL). The mixture is extracted with EtOAc three times and the combined organic phase is washed with water (10 mL) twice. The organic phase is then dried over Na2SO4 and concentrated. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:9) to give 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine. MS (ESI) m/z 458.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH:13]([Br:15])[CH3:14])[N:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(Cl)ccnc1CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)ccnc1C(C)Br

Procedure:
A mixture of the above ethylnicotinate (5.45 g), N-bromosuccinimide (NBS) (5.50 g) and 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.40 g) in carbon tetrachloride (50 ml) is heated under reflux for 2 hours, then cooled, filtered and concentrated in vacuo to give ethyl 4-chloro-2-(1-bromoethyl)nicotinate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH:25]1([CH2:28][NH:29][CH2:23][C:20]2[CH:21]=[CH:22][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)[CH:19]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1ccc(CNCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with cyclopropanemethylamine (50 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 189 (0.01 g, 14%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CS(C)=O>[O:19]1[CH2:20][CH2:21][N:16]([C:2]2[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1C(F)(F)F
Yield: 95.8 %

Procedure:
Add ethyl 2-chloro-4-(trifluoromethyl)thiazole-5-carboxylate (4.00 g, 15.4 mmol) to a solution of morpholine (4.03 g, 46.2 mmol) in DMSO (10 mL). Stir the reaction at ambient temperature overnight. Add CH2Cl2, and wash the mixture with H2O. Dry the organic phase over Na2SO4, filter, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (20:5:1 hexanes:EtOAc:2 M NH3/MeOH) to yield the title compound (4.58 g, 96%). ES/MS m/z 311.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[NH:8]2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.Br[CH2:29][CH2:30][O:31][CH3:32]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][CH2:17]3)[N:8]2[CH2:29][CH2:30][O:31][CH3:32])=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:3]=1
Reactant: COCCBr
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3[nH]2)CC1
Product: COCCn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
4-(2-chloro-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (215 mg) was reacted with 2-bromoethylmethylether via General Procedure C to give 4-(2-chloro-9-(2-methoxyethyl)-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (207 mg) which was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A and purified via reverse phase HPLC to give 21.6 mg 133 as a white solid. MS (Q1) 556.3 (M)+.
Reaction SMILES: [CH3:1][C:2]([CH3:53])([CH3:52])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[N:26]=[CH:25][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:23]=4)[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:8]=1)=[O:5]>Cl.O1CCOCC1>[NH:24]1[CH:25]=[N:26][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:52])([CH3:1])[CH3:53])[CH:12]=[CH:11][CH:10]=2)=[N:23]1
Reactant: CC(C)(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
3,3-Dimethyl-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)butanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and was purified by preparative HPLC (0.027 g, 29% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.15 (s, 1H), 8.10 (d, 1H), 7.75 (t, 2H), 7.69 (d, 1H), 7.51 (t, 1H), 2.30 (s, 2H), 1.12 (t, 9H); ES-MS (m/z) 375 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]2[CH:15]=[C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][C:10]=2[NH:11][N:12]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:7][C:8]1[C:9]2[CH:15]=[C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][C:10]=2[N:11]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[N:12]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc2c(N)n[nH]c2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
A solution of ethyl chlorocarbonate (4.90 mL, 51.7 mmol) in tetrahydrofuran (THF, 60 mL) was slowly added to a mixture of tert-butyl 3-amino-1H-thieno[2,3-c]pyrazole-5-carboxylate (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 mL, 301 mmol) in THF (300 mL), maintaining the temperature between −5 and −10° C. The reaction was kept at the same temperature for 5 minutes then allowed to reach room temperature. The obtained mixture was evaporated to dryness under vacuum and the residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The resulting raw material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5](OC1C=CC=CC=1)[CH:6]=[CH2:7].C([O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([Cl:26])=[C:21]([CH3:27])[CH:20]=1)C=C>>[CH2:7]([C:24]1[C:23]([CH3:25])=[C:22]([Cl:26])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:18])[CH:6]=[CH2:5]
Reactant: C=CCOc1cc(C)c(Cl)c(C)c1
Reactant: C=CCOc1ccccc1
Agent: ClB(Cl)Cl
Product: C=CCc1c(O)cc(C)c(Cl)c1C

Procedure:
These o-allyl phenols are accessible in a simple and conventional manner by the Claissen transposition from the corresponding phenol allyl ethers at elevated temperature or in the cold in the presence of boron trichloride, it being necessary, of course, to take into account the different reactivities of the various phenols (cf. Houben-Weyl, Phenole I). For example, the transposition of phenol allyl ether requires 200° C. for about 10 hours, giving an approximately quantitative yield. On the other hand, 4-chloro-3,5-xylenol allyl ether reacts completely within 2 hours, and the 2-allyl-4-chloro-3,5-xylenol (MP 65° C.) can be isolated in an approximately quantitative yield only when the heat treatment is immediately stopped thereafter, on account of the threat of isomerization to the corresponding benzodihydrofuran (MP 36° C.). On the other hand, 2,4,5-trichlorophenol allyl ether is transposed above 150° C. in a very violent and highly exothermic reaction; this is mentioned especially for safety reasons.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][N:15]([N:17]=O)[CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)(=O)C.[Zn]>[CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][N:15]([NH2:17])[CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCN(N=O)CC1C(=O)NCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCN(N)CC1C(=O)NCc1ccccc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a mixture of rac-N-benzyl-1-acetyl-4-nitrosopiperazine-2-carboxamide (655 mg) in water (2 ml) and acetic acid (0.65 ml) was added zinc powder (443 mg) as portions during the period of 2 hours at 8-13° C. (exothermic reaction) with ice-water cooling bath. After removal of the bath, the temperature was raised till 55° C. and the reaction mixture was additionally stirred at 30-40° C. for 2 hours. The zinc residue was filtered off and washed with methanol (50 ml) on the Celite. The combined filtrate was added into dichloromethane (40 ml) and sodium hydroxide (460 mg) in water (6 ml) below 35° C. The resulting precipitate was filtered off with Celite and the residue was washed with chloroform (50 ml). The combined filtrate was washed with water, dried over magnesium sulfate and concentrated to give rac-N-benzyl-1-acetyl-4-aminopiperazine-2-carboxamide (274 mg). This product was used for next step without purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH3:10][C:11]([O:18][OH:19])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C1(O)C=CC=CC=1>>[C:11]([O:18][O:19][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:17])[CH3:10]
Reactant: CC(C)(C)CC(C)(C)OO
Reactant: C=C(C)c1ccccc1
Solvent: Oc1ccccc1
Product: CC(C)(C)CC(C)(C)OOC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
Into the 200 ml jacketed reactor described in Example II were added 18.0 grams (0.152 m) alpha-methylstyrene, 18.4 grams (0.11 m) 87.6% 1,1,3,3-tetramethylbutyl hydroperoxide and 4.6 grams (0.048 m) phenol. The mixture was stirred to obtain a clear solution and the temperature was adjusted to 20° C. To this solution was added 1.7 grams (0.011 m) of t-cumyl chloride from the addition funnel over 5 minutes while holding the temperature at 20°-21° C. The reaction was stirred 5 minutes at 21°-22° C., warmed to 25° C. and stirred 1/2 hour at 25° C., 1/2 hour at 30° C., 1/2 hour at 35° C., 11/2 hours at 40° C. and finally 1/2 hour at 45° C. At this point the t-octyl hydroperoxide had been completely consumed and the reaction was terminated by adding 50 mls of water, stirring 5 minutes, adding 10 mls of 50% NaOH, stirring another 5 minutes and separating the aqueous caustic layer. The organic layer was successively washed with 50 mls 15% NaOH, saturated NaHCO3 solution, H2O, 15% NaHSO3 solution, saturated NaHCO3 solution and water. After drying over anhydrous sodium sulfate the crude product weighed 32.6 grams and contained 72.6% cumyl t-octyl peroxide for a corrected yield of 23.7 grams and a 81.5% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]([O-:10])([O-])=O.[Na+].[Na+].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:17]=1C(O)=O)([O-:15])=[O:14]>[N+](C1C=C([N+]([O-])=O)C=CC=1C(Cl)=O)([O-])=O>[N+:13]([C:16]1[CH:17]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:23][C:24]=1[C:7]([NH:1][C@@H:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:10])([O-:15])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O

Procedure:
The reaction of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 2 g and SOCl2, 20 mL) with L-alanine (1.04 g, 11.79 mmol) in the presence of Na2CO3 (1.24 g, 11.79 mmol) as described in intermediate 2 gave the title compound as an off-white color solid (2.08 g, 78%), mp 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 12.77 (1H, s), 9.25 (1H, d, J=7.6 Hz), 8.77 (1H, d, J=2.0 Hz), 8.63 (1H, dd, J=8.4, 2.0 Hz), 7.87 (1H, d, J=8.4 Hz), 4.44 (1H, pentet, J=7.3 Hz), 1.38 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 282 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1(CC(N)=O)[C:14](=O)[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1.[OH-].[Na+].CC1([NH2:32])CC2C(=CC=CC=2)C1>C(O)(=O)C.OS(O)(=O)=O>[CH3:1][C:2]1([NH2:32])[CH2:14][C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1
Reactant: CC1(CC(N)=O)Cc2cc3c(cc2C1=O)CCCC3
Reactant: CC1(N)Cc2ccccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(N)Cc2cc3c(cc2C1)CCCC3

Procedure:
A 4:1 mixture of geometrical isomers, containing predominantly 2,2,2-trifluoro-.N.-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-acetamide, is hydrogenated over PD/C in acetic acid/H2SO4 and the products are saponified with NaOH according to the procedures described for the preparation of 2-methyl-indan-2-ylamine. The resulting product mixture is recrystallised repeatedly from hexane to give the title compound, a single isomer.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:8])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(NN)cc1
Product: CCOC(=O)CN(N)c1ccc(C)cc1

Procedure:
Method for the preparation of compound 19 [isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate]: p-tolylhydrazine is alkylated with ethyl 2-bromoacetate to give the substituted phenylhydrazine, ethyl 2-(1-p-tolylhydrazinyl)acetate (III). The reaction of III with 4,4-dimethoxy-N-methylbutan-1-amine gives the indole derivative ethyl 2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V). Effecting the indole to standard Pictet Spingler conditions with formaldehyde gives the 1-carboline intermediate (VI) ethyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. Following treatment of VI with base the acid (VIII) 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acid is obtained. The treatment of this acid with DCC or other standard coupling reagents with 3-methylbutan-1-ol gives compound 19 isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.NC1N=[C:25]([C:27]2C=C(Br)C=CC=2O)[CH:24]=[C:23](Cl)N=1.C(O)C1C=CC=CC=1>>[CH2:17]([O:16][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=1)[C:18]1[CH:27]=[CH:25][CH:24]=[CH:23][CH:19]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Solvent: OCc1ccccc1
Product: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCc2ccccc2)n1
Yield: 43 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and benzyl alcohol provided 4-(2-benzyloxy-5-bromo-phenyl)-6-chloro-pyrimidin-2-ylamine (43% yield).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[OH:29])([O-:22])=[O:21].[OH-].[K+]>CS(C)=O>[N+:17]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:25]1[CH:26]=[CH:27][C:28](=[O:29])[C:23]([N+:20]([O-:22])=[O:21])=[CH:24]1)[N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(=O)c([N+](=O)[O-])c3)cc21
Yield: 91 %

Procedure:
First, 803 mg of 7-fluoro-6-nitro-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione, 700 mg of 3-nitro-4-hydroxypyridine, and 365 mg of potassium hydroxide were allowed to react at 130° C. for 4.5 hours in dry dimethylsulfoxide in the same way as in Example 9 to give 1.059 g of 6-nitro-7-(3-nitro-4-oxo-4H-pyridin-1-yl)-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: C(O[P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]1[C:15](=[O:41])[N:16](O)[C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:19]([C:36]([F:39])([F:38])[F:37])[CH:18]=2)=O)([O:6]CC)=[O:5])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:61](O)(=[O:63])[CH3:62]>>[CH2:61]([O:63][C:9](=[P:4]([OH:6])=[O:5])[C:10]1[N:23]2[C:22]3[C:17]([NH:16][C:15](=[O:41])[C:14]2=[N:13][N:12]=1)=[CH:18][C:19]([C:36]([F:39])([F:38])[F:37])=[C:20]([N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:21]=3)[CH3:62]
Reactant: CC(=O)O
Reactant: CCOP(=O)(CC(=O)NNc1nc2cc(-n3cc(C)nc3-c3ccccc3)c(C(F)(F)F)cc2n(O)c1=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(c1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(-n4cc(C)nc4-c4ccccc4)cc3n12)=[P+]([O-])O

Procedure:
A solution of 3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-1-hydroxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one (1.5 g, 2.5 mmol) and triphenylphosphine (1.3 g, 5 mmol) in 50 ml of glacial acetic acid was stirred overnight at 120° C.