Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][N:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])nc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])nc1

Procedure:
To 6-nitronicotinic acid (3.5 g) is added thionyl chloride (50 ml), and the mixture is refluxed for three hours, and evaporated to remove thionyl chloride to give 6-nitronicotinoyl chloride, which is added with stirring to a solution of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (3.4 g) in pyridine (50 ml) under ice-cooling. The mixture is stirred at room temperature overnight. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (4.9 g) as colorless amorphous.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1>C(Cl)Cl>[C:8]([NH:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(N)no1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)no1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Triethylamine (10 ml., 71.9 mmol) is added dropwise to an ice cold solution of 20.0 g. (71.6 mmol) of trityl chloride in 200 ml. of methylene chloride and the resulting solution is stirred at ice bath temperature for 5 minutes. 3-Amino-5-methylisoxazole (7.0 g., 71.5 mmol) in 50 ml. of methylene chloride is then added dropwise over 10 minutes. After the addition, the ice bath is removed and the stirring continued for 1.5 hours. The solution is washed with ice cold 1N HCl, dried (MgSO4) and the solvent concentrated under reduced pressure until a white solid is present. Diethyl ether is added and the solid collected and dried to give 21 g. (85%) of the title compound as a white crystalline material; m.p. 196°-199° C.
Reaction SMILES: FC1C2OC(CN)CNC=2C=CC=1.[CH3:14][N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH:17]([C:25]([NH2:27])=O)[CH2:16]1>>[CH3:14][N:15]1[CH:20]2[CH2:21][CH:22]=[CH:23][CH:24]=[C:19]2[O:18][CH:17]([CH2:25][NH2:27])[CH2:16]1
Reactant: CN1CC(C(N)=O)Oc2ccccc21
Agent: NCC1CNc2cccc(F)c2O1
Product: CN1CC(CN)OC2=CC=CCC21

Procedure:
This compound is obtained following the same experimental conditions as those used for the synthesis of intermediate 2b but replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-carboxamide (4b) with 3,4-dihydro-4-methyl-2H-1,4-benzoxazine-2-carboxamide (4g) [84831-37-8]. The title compound of formula (2g) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:36][C:37]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:43][C:37]5([CH3:36])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCCCC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 29.1 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.22 mmol) in 6 mL of DMF were added EDCI (64 mg, 0.33 mmol) and DMAP (42 mg, 0.34 mmol), followed by the addition of 1-methylcyclohexanamine hydrochloride (50 mg, 0.33 mmol) in one portion at room temperature and stirred for 16 hours. The reaction mixture was poured into 35 mL of water, and filtered to give a crude product, which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 88% acetonitrile/12% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 28.4%) as a pale yellow solid. MS: (M+H)+=407; 1H NMR (300 MHz, DMSO): δ 12.68 (s, 1H), 9.10 (s, 1H), 8.45-8.40 (m, 2H), 7.85 (s, 1H), 7.71 (d, 1H, J=9.9 Hz), 7.20-7.14 (m, 1H), 4.17 (s, 3H), 2.33-2.29 (m, 2H), 2.03-2.00 (m, 1H), 1.53-1.46 (m, 10H).
Reaction SMILES: BrC1C=CC2OCCN3C(I)=C(C(N)=O)N=C3C=2C=1.Cl.NC1CCOCC1.Br[C:29]1[CH:30]=[CH:31][C:32]2[O:38][CH2:37][CH2:36][N:35]3[C:39]([C:45]([NH:47][CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[O:46])=[C:40]([C:42]([NH2:44])=[O:43])[N:41]=[C:34]3[C:33]=2[CH:54]=1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C@:61]([OH:65])([C:63]#[CH:64])[CH3:62])[CH:57]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CS(C)=O>[OH:65][C@:61]([C:58]1[CH:57]=[C:56]([CH3:55])[O:60][N:59]=1)([CH3:62])[C:63]#[C:64][C:29]1[CH:30]=[CH:31][C:32]2[O:38][CH2:37][CH2:36][N:35]3[C:39]([C:45]([NH:47][CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[O:46])=[C:40]([C:42]([NH2:44])=[O:43])[N:41]=[C:34]3[C:33]=2[CH:54]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CS(C)=O
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Temperature: 40 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
Similar to as described in Example 10 (carbonylative amidation) a mixture of 10-bromo-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (200 mg, 0.46 mmol, 1.00 equiv), 4-aminotetrahydropyran hydrochloride (126 mg, 0.92 mmol, 2.00 equiv), Pd(dppf)Cl2 (34 mg, 0.05 mmol, 0.10 equiv), TEA (202 mg, 2.00 mmol, 4.00 equiv), and DMSO (5 mL) was stirred at 40° C. under an atmosphere of CO(g) overnight. The reaction was quenched with water and the solids were collected. This resulted in 250 mg (crude) of 10-bromo-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide as a brown solid. Similar to as described General Procedure F, 10-bromo-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (38.6 mg, 6.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)C.C(=O)=O.[Br:32]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:32])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(N)ncnn23)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 134.1 %

Procedure:
To a solution of 4-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (252 mg, 0.758 mmol) in THF (8 mL) at −20° C. (IPA and dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (108 mg, 0.379 mmol). The reaction was stirred at −20° C. for 4 h. After removal of solvent, the residue was purified by silica gel column using 4% methanol in dichloromethane to obtain 209 mg (67%) of desired product. 1H-NMR (CD2Cl2) δ 7.81 (s, 1H), 7.23 (s, 1H), 6.61 (s, 1H), 3.86 (s, 1H), 3.41 (t, J=2.4, 4H), 2.48 (s, 4H), 1.43 (s, 9H) MS [M+H]+=410.9; LCMS RT=1.87 min
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:17])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1O>>[CH3:4][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:21]1[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=1[Cl:19])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(O)c1nccs1
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Product: CC(C)(C)OC(=O)NCCCC(Oc1cc(C(F)(F)F)ccc1Cl)c1nccs1

Procedure:
The subtitle compound was prepared according to the method of Example 19 step (b) using the product of Example 43 step (c) and 2-chloro-5-trifluoromethylphenol.
Reaction SMILES: C(O[C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=1)C1C=CC=CC=1.[C:20]([O:25][CH2:26][C@H:27]1[O:29]C1)(=[O:24])CCC>>[F:18][C:13]1[CH:12]=[C:11]([N:10]2[CH2:9][C@@H:26]([CH2:27][OH:29])[O:25][C:20]2=[O:24])[CH:16]=[CH:15][C:14]=1[CH3:17]
Reactant: CCCC(=O)OC[C@@H]1CO1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Product: Cc1ccc(N2C[C@@H](CO)OC2=O)cc1F

Procedure:
Starting from (3-fluoro-4-methyl-phenyl)-carbamic acid benzyl ester (prepared from 3-fluoro-4-methyl-aniline and CbzCl according to procedure C) and (S)-glycidyl butyrate and following the procedure described for the preparation of intermediate 1.iii)(procedure D), the title compound was obtained as a yellow solid (4.16 g, 65%).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:9][C@H:8]2[N:10]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])C(=O)OC(C)(C)C)=[CH:3][CH:2]=1.O(CC)CC.Cl>CCOCC>[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:2]=[CH:3][C:4]([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])=[CH:5][CH:6]=1
Reactant: CN1CCN(C(=O)CN(C(=O)OC(C)(C)C)[C@@H]2C[C@H]2c2ccc(-c3ccccc3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Product: CN1CCN(C(=O)CN[C@@H]2C[C@H]2c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of tert-butyl(trans)-2-(1,1′-biphenyl-4-yl)cyclopropyl(2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamate derivative (1 equiv) in Et2O at 0° C. was added Et2O.HCl slowly drop wise, stirred for 1 h at 0° C. to RT. The progress of the reaction was monitored by TLC. After completion reaction mixture was filtered under inert atmosphere and washed with hexane and EtOAC, and dried under reduced pressure to get 2-((trans)-2-(1,1′-biphenyl-4-yl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanone derivative (Overall yield 15%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1O

Procedure:
2-Hydroxyphenylacetic acid (6.06 g, 39.8 mmol) was dissolved in ethanol (180 ml) and the solution was added with concentrated sulfuric acid (2 ml) and heated under reflux for 90 minutes. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound as orange oil (7.67 g, yield: quantitative).
Reaction SMILES: [CH2:1]([O:9][C:10]([CH:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:22])=O>>[CH2:1]([O:9][C:10]([CH:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14]([Cl:22])=[O:15])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOC(=O)C(C)C(C)(C)C(=O)O
Product: CCCCCCCCOC(=O)C(C)C(C)(C)C(=O)Cl

Procedure:
3-(1-Octyloxycarbonyl)-2,2-dimethylbutyric acid (0.4 g) was treated with thionyl chloride (20 ml) and the excess thionyl chloride was removed in vacuo to afford 0.33 g of 3-(1-octyloxycarbonyl)-2,2-dimethylbutyric acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:37])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccccn2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and picolinic acid (9 mg, 0.07 mmol). Yield 14 mg (39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-(4-Benzyloxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (40a, 3.0 g, 7.84 mmol) was dissolved in CH2Cl2 (50 mL) and treated with isovaleraldehyde (0.84 mL, 7.84 mmol). The reaction was stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3, and stirred overnight. The reaction was diluted with EtOAc (400 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 6% MeOH/CH2Cl2 to give 3.3 g (93%) of the desired product.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:14])[NH2:13].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[OH:28])=O>O>[OH:28][C:22]1[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=1[CH2:19][CH2:18][NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:14]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N=C(N)NCCC[C@H](NCCc1ccc(O)cc1O)C(=O)O
Reaction time: 1 h

Procedure:
Ingredients. (1) Water 95.5 (2) Sodium Bicarbonate 0.9 (3) Arginine.2H2O 2.1 (4) Resacetophenone 1.5. Procedure. Mix (1) to (3). Heat to 70 to 80 C. Add (4). An instantaneous reaction occurs and a clear yellow solution is obtained. The mixing and heating is continued for 1 hour, and then hydrogenated over Pt catalyst. After filtration of catalyst, solution of N-[(2,4-dihydroxyphenyl)ethyl]arginine Sodium in water is thus obtained, pH 9.5. Water is evaporated to ⅓ in volume and the solution allowed to cool. The pH is adjusted to 6.5 with citric acid (2.0 grams of 50% solution). N-[(2,4-dihydroxyphenyl)ethyl]arginine is obtained as an off-white to pale, yellow crystalline solid, which is used directly in the preparation of cosmetic compositions.
Reaction SMILES: C([O:4][CH:5]1[CH2:22][CH2:21][C:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C:10]3([CH3:48])[CH:19]2[CH2:18][CH2:17][CH:16]2[C:11]3([CH3:47])[CH2:12][CH2:13][C:14]3([C:30](=[O:46])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][CH:24]([C:27]([CH3:29])=[CH2:28])[CH:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([CH2:37][C@H:34]2[CH2:35][CH2:36][C@@H:32]([NH:31][C:30]([C@:14]34[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:47])([CH2:12][CH2:13]4)[C@@:10]4([CH3:48])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:46])[CH2:33]2)[CH2:39][CH2:40]1)[CH3:45]
Reactant: C=C(C)C1CCC2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CCC3(C)C(CCC4C5(C)CCC(OC(C)=O)C(C)(C)C5CCC43C)C12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-3-((4-ethylpiperazin-1-yl)methyl)cyclopentylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 34, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); MASS: 650 (100%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:20])([F:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.Cl>CO>[F:20][C:4]([F:3])([F:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: O=C1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Sodium borohydride (324 mg, 8.56 mmol) was added to a solution of 1-(4-trifluoromethoxyphenyl) piperidin-4-one (1.11 g, 4.28 mmol) prepared in Reference Example 22 in methanol (30 ml) while cooling in an ice-bath, and the mixture was stirred for 30 minutes. To which 10% hydrochloric acid was added, and the resulting mixture was concentrated under reduced pressure. To the residue saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 1-(4-trifluoromethoxyphenyl)piperidin-4-ol (1.08 g, yield 97%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]1>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([O:28][CH2:11][CH2:6][CH2:7][CH3:8])=[O:27])[CH2:20][CH2:19]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(O)CCC1CCNCC1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)CCC1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Yield: 114.7 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (24.9 g) and 3-(4-piperidinyl)propionic acid, hydrochloride (20 g) in n-butanol (1000 ml) were stirred under reflux for 20 hours. The hot suspension was filtered and the insoluble material discarded. The filtrate was cooled in ice/water, the precipitated solid collected and the filtrate evaporated in vacuo. The resulting solid and the precipitated solid were combined and crystallised from isopropanol to give 4-amino-2-[4-(2-{n-butoxycarbonyl}ethyl)piperidino]-6,7-dimethoxyquinazoline, hydrochloride (27.0 g) with m.p. 250°-252°.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17]([OH:19])=[CH:16][CH:15]=[CH:14]2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[Na+].Cl.C(O)[CH2:27][O:28]CCO>O>[CH2:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17]([OH:19])=[C:16]([O:28][CH3:27])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc2cccc(O)c12
Reactant: OCCOCCO
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
122 g of 8-benzoyl-1-naphthol was suspended in 800 ml of diethylene glycol, followed by the addition of 250 ml of hydrazine monohydrate and 99 g of sodium hydroxide at room temperature. The obtained mixture was stirred at 100° C. for 48 hours and cooled to room temperature by allowing to stand, followed by the addition of 500 ml of water. The obtained mixture was acidified with concentrated hydrochloric acid and extracted with 1.5 l of toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride and purified by silica gel column chromatography (developer: benzene) to give 100 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([CH:25]([CH3:27])[CH3:26])[CH2:21][C:22]([NH2:24])=[O:23]>>[C:22]([CH2:21][C@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:25]([CH3:27])[CH3:26])(=[O:23])[NH2:24]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)[C@@H](N)CC(N)=O
Agent: Cl
Product: CC(C)[C@H](CC(N)=O)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6 using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and (3S)-3-amino-4-methyl-pentanamide monohydrochloride (CAN 173336-51-1, 39 mg, 0.24 mmol) as starting materials and isolated (55 mg, 74%) as light yellow solid; LC-MS (UV peak area, ESI) 98%, 347.2082 (M+H)+.