Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: N#CCc1ccc(Br)cc1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 100 °C

Procedure:
A solution of 8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (as prepared by PCT Int. Appl. WO2006064189, 1.81 g, 6.80 mmol), 4-bromo-phenyl-acetonitrile (Aldrich, 1.40 g, 7.10 mmol), and tetrakis(triphenylphosphino)-palladium(0) (Aldrich, 350 mg, 0.34 mmol) in 1,4-dioxane (20 mL), was treated with 2M aqueous Na2CO3 (7 mL, 14.0 mmol), bubbled with argon for a few minutes, and heated to 100° C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL) and extracted thrice with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo to give a colorless oil. Purification by silica gel column, using a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate), afforded the title compound as a white solid.
Reaction SMILES: FC1C=CC(CN2CCN(C(CNS(C3C=CC(OCC4C5C(=CC=CC=5)N=C(C)C=4)=CC=3)(=O)=O)C(O)=O)CC2)=CC=1.[F:43][C:44]1[CH:85]=[CH:84][C:47]([CH2:48][N:49]2[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:60][NH:61][S:62]([C:65]3[CH:70]=[CH:69][C:68]([O:71][CH2:72][C:73]4[C:82]5[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=5)[N:76]=[C:75]([CH3:83])[CH:74]=4)=[CH:67][CH:66]=3)(=[O:64])=[O:63])[C:56]([NH:58][OH:59])=[O:57])[CH2:51][CH2:50]2)=[CH:46][CH:45]=1>>[F:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:48][N:49]2[CH2:54][CH2:53][N:52]([CH:55]([CH2:60][NH:61][S:62]([C:65]3[CH:66]=[CH:67][C:68]([O:71][CH2:72][C:73]4[C:82]5[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=5)[N:76]=[C:75]([CH3:83])[CH:74]=4)=[CH:69][CH:70]=3)(=[O:63])=[O:64])[C:56]([NH:58][OH:59])=[O:57])[CH2:51][CH2:50]2)=[CH:84][CH:85]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1
Agent: Cc1cc(COc2ccc(S(=O)(=O)NCC(C(=O)O)N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)NCC(C(=O)NO)N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1

Procedure:
In a manner analogous to example 3.8, using 990 mg (1.7 mmol) of (S)-2-[4-(4-fluorobenzyl)-piperazin-1-yl-3-(4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoic acid, 330 mg (33%) of (S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the form of a white solid with a melting point of 180° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1)(=O)C.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[N:19]([CH:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: CC(=O)OC1CCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c(F)cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
A 1.32 g quantity of N,O-bis(trimethylsiliyl)-acetamide was added with stirring to a suspension of 0.40 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 8 ml of dry dichloromethane at room temperature. To the mixture were added, after 4 hours, 0.32 g of 2-acetoxytetrahydrofuran and a solution of 0.1 ml of stannic chloride in 1.6 ml of dry dichloromethane. The mixture was stirred for 1.5 hours and neutralized with 0.64 ml of triethylamine and washed with water. The dichloromethane layer was concentrated and the residue was dissolved in 16 ml of methanol. To the solution was added 0.24 ml of acetic acid and the mixture was left to stand for 3 hours at 40° C. The solvent was distilled off and the residue was subjected to silica gel column chromatography to conduct a gradient elution using chloroform and mixtures of methanol (up to 4%) and chloroform, giving 0.3 g of the title compound in a yield of 77%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])=[O:10]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: NCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1F)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
In a flask were placed 4 grams (g) (0.01326 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride, dissolved in methylene chloride. There was then added 1.7 g (0.01326 mole) of 2-fluorobenzylamine, very slowly, with vigorous stirring. After about 15 minutes, 1.34 g (0.01326 mole) of triethylamine was added dropwise. The reaction mixture was stirred for a short time, then heated intensely for about 5 minutes and allowed to return to room temperature. After approximately 1/2 hour, 5% aqueous sodium carbonate solution was added with stirring continued. The aqueous and organic phases were separated; the aqueous phase was decanted off and the organic phase washed twice with 5% sodium carbonate solution and twice with water. The organic phase was then dried over sodium sulfate; solvent was stripped off, and an oil-like mixture was recovered, which crystallized in a short time. The solid was then washed with pentane to remove any remaining amine. There was obtained 3.5 g (67% of theoretical yield) which was identified as the desired compounds by infrared, nuclear magnetic resonance, and mass spectroscopic analysis.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[C:24]([S:32][CH2:33][C@H:34]([CH3:38])[C:35](Cl)=[O:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:7]([C:35](=[O:36])[C@H:34]([CH3:38])[CH2:33][S:32][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: CCCCN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Yield: 73.4 %

Procedure:
3.0 g of tert.-butyl (4S)-1-n-butyl-2-oxo-imidazolidine-4-carboxylate, 1.4 g of potassium tert.-butoxide, (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared from 2.8 g of (2S)-3-benzoylthio-2-methylpropionic acid and 10 ml of thionyl chloride) and 40 ml of tetrahydrofuran are treated in the same manner as described in Example 2-(2). Then, the oily residue obtained is purified by silica gel chromatography (Solvent, toluene-ethyl acetate (20:1)). 3.8 g of tert.-butyl (4S)-1-n-butyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1>C(Cl)Cl.CO>[NH2:1][CH2:2][CH:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1

Procedure:
4-Amino-1-tert-butyloxycarbonylazacycloheptane colourless oil; RF : 0.36 (alumina; methylene chloride/methanol=9:1)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[O-2].[O-2].[Hf+4]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [Hf+4]
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 140° C. with 14.1 g of a powdered hafnium dioxide from the Aldrich company. After 2 h reaction time, the phenol conversion was 3.7%, whereby 3.5 g phenyl chloroformate and 3.3 g diphenyl carbonate were formed. The selectivity to carbonate esters was ca. 97%.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OCC)OCC>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: CCOP([O-])OCC
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 196 °C
Yield: 75 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of diethyl phosphite are mixed and heated to 196° C. The elimination of water commences at this temperature and has ended when the internal temperature is 234° C. 27 parts of water are removed in the course of 8 hours. After distilling off excess α-naphthol and aniline, 330 parts of phenyl-α-naphthylamine are obtained at a boiling point of 203° - 205° C/5 mm Hg; the product has a melting point of 54° - 58° C and corresponds to a yield of 75% of theory.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[N:5]([CH3:7])[CH3:6].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([C:2]1[CH:3]=[C:4]([N:5]([CH3:7])[CH3:6])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[OH:24]
Reactant: COc1ccc(N(C)C)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(N(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 80.2 %

Procedure:
With 500 mg of the compound obtained in Step 190-2 and 270 mg of 5-chloroisatin as starting materials, 397 mg of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of yellow mercuric oxide (1.18g, 0.0054mol), N-[3-(2-,6-dichlorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (2.0g, 0.0045mol) and methanolic ammonia solution (40 ml) was stirred for 5 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 1.54 g (81%), m.p. 192°-195 ° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:45][C:46]1[N:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:8]([C:19](=[O:20])[NH:53][CH2:52][C:49]3[CH:50]=[N:51][C:46]([CH3:45])=[CH:47][CH:48]=3)[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: Cc1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (1.5 g, 5.3 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.0 g, 10 mmol), 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and CH2Cl2 (50 mL) were added (6-methylpyridin-3-yl)methanamine (0.97 g, 7.9 mmol) and N,N-diisopropylethylamine (1.8 mL, 10 mmol). The mixture was stirred at room temperature for 4 h, and then washed with water and aq. Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column to afford a white foam.
Reaction SMILES: [ClH:1].FC1C=C([CH:29]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[O:34])[C:30](N)=[O:31])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:45]=[C:46]([NH2:71])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:70])[C:58]([O:60][CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]3)=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1>>[ClH:1].[ClH:1].[F:43][C:44]1[CH:45]=[C:46]([NH:71][C:30](=[O:31])[CH2:29][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[O:34])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:70])[C:58]([O:60][CH2:61][CH2:62][N:63]3[CH2:64][CH2:65][N:66]([CH3:69])[CH2:67][CH2:68]3)=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Yield: 46 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 36, 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (60 mg, 0.15 mmol) was converted the title compound (30 mg, 46%) as a 2.HCl salt. 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 10.37 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.80 (d, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 7.16 (m, 2H), 4.42 (br s, 2H), 3.38-3.60 (m, 10H), 2.81 (s, 3H), 2.40 (s, 3H);). MS(ESI+) m/z 580.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:13]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@@H:15]([NH:17][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)N)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2ccc3ccn(C[C@H](C)NC(=O)C(F)(F)F)c3c2c1
Yield: 58.5 %

Procedure:
A solution of 1.5 g of (S)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine, 0.74 g of triethylamine and 1.04 g of ethyl trifluoroacetate in 100 ml of anhydrous methanol was stirred at room temperature for 27 hours. After the solvent had been drawn off in a vacuum, the residue was taken up with 100 ml of ahydrous dioxane, 1.56 g of DDQ were added and the mixture was boiled under reflux for 1.5 hours. Subsequently, the reaction mixture was concentrated in a vacuum and the residue was purified by column chromatography on silica gel (dichloromethane/acetone 4:1). 1.2 g (59%) of (S)-N-[2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethyl]-trifluoracetamide were obtained as a pale brown solid which was used in the next reaction without additional recrystallization.
Reaction SMILES: O1[C:10]2[C:5](=[CH:6]C=CC=2)[CH2:4]CC1.COCOC1C(C)=C2C(=C(C)C=1C)OC(CCN1CCNCC1)(C)CC2.[C:37]1(=[O:52])[N:41]([O:42][CH2:43][C:44]([OH:46])=[O:45])[C:40](=[O:47])[C:39]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:38]12.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CO.CCOC(C)=O>[C:40]1(=[O:47])[N:41]([O:42][CH2:43][C:44]([O:46][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:45])[C:37](=[O:52])[C:38]2=[CH:51][CH:50]=[CH:49][CH:48]=[C:39]12
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C(O)CON1C(=O)c2ccccc2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCOc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 143.7 %

Procedure:
To a solution of chroman (compound 5) (5.0 g, 13.8 mmole) in dichloromethane (30 ml), compound 7 (3.5 g, 16 mmole) and N-hydroxysuccinimide (1.8 g, 16 mmole) were added, as shown in FIG. 7. The mixture was stirred at room temperature until the formation of a clear solution and then 1,3-dicyclohexylcarbodiimide (16 ml, 1.0 N in dichloromethane, 16.0 mmole) was added. The mixture was stirred at room temperature overnight. The white solid was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (100 ml), and the solution was washed by saturated NaHCO3 (100 ml) and H2O (100 ml). The organic solvent was evaporated to dryness to give a yellow glass. This yellow glass was passed through a silica column with MeOH/EtOAc (5/95) to give a yellow glass as product 8 (5.5 g, 70% yield). The compound was characterized as NMR and MS as follows: 1) C-NMR (CDCl3): 11.983, 12.861, 13.729, 20.117, 23.550, 30.055, 35.951, 41.494, 45.291, 52.196, 52.087, 57.051, 73.411, 75.309, 99.049, 116.801, 122.420, 123.437, 125.719, 127.671, 128.283, 134.187, 146.465, 147.220, 162.451, 163.470 ppm; 2) H-NMR (CDCl3): 1.244 (s, 3H), 1.790 (m, 4H), 2.052 (s, 3H), 2.119 (s, 3H), 2.157 (s, 3H), 2.9-2.6 (m, 8H), 3.586 (s, 3H), 3.62 (b, 2H), 3.72 (b, 2H), 4.813 (s, 2H), 4.825 (s, 2H), 7.726 (m, 2H), 7.803 (m, 2H) ppm; and 3) MS (ESI): 566.4 [M+H]+, 588.4 [M+Na]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:26])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH3:25]
Reactant: CCOc1cc(Nc2cccc(C(=O)OC)c2C(=O)OC)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(Nc2cccc(C(=O)O)c2C(=O)O)ccc1OC
Yield: 85.5 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenylamino)phthalic acid dimethyl ester (0.85 g, 2.4 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 3 hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.68 g of the product, in 87% yield: 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H), 3.73 (s, 3H), 3.96 (q, J=6.9, 2H), 6.69 (dd, J=8.6 Hz, J=2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 7.00 (d, J=7.2 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.97 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:5][C:4]=1[Br:17].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:5][C:4]=1[Br:17]
Reactant: Nc1c(F)cc(C(=O)CNC2CC2)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(F)cc(C(O)CNC2CC2)cc1Br

Procedure:
m.p. of the hydrochloride: 185°-187° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-cyclopropylamino-5'-fluoro-acetophenone and sodium borohydride analogous to Example 1.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CCOCC.CO>[OH:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1
Reactant: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CCN2C[C@@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To 870 mg (1.63 mmol) of (+)-5-[[(2R,4S)-4-benzoyloxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine in 15 ml of ether was added 460 mg (11.4 mmol) of NaOH in methanol (60 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, then water was added to the residue and the products were extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate) to give 680 mg (97.1%) of (+)-5-[[(2R,4S)-4-hydroxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as yellow amorphous.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[C@@H:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:23]=1[F:30].[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:14][C@H:5]1[CH2:4][C@@H:3]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6]1=[O:13]
Reactant: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl]carbamate (402 mg, 0.913 mmol) in EtOAc (10 mL) was saturated with HCl(g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=341.0 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.20 (m, 1H), 6.94 (m, 1H), 4.78 (dq, 1H, J=15.4, 9.3 Hz), 4.26 (dd, 1H, J=12.1, 6.7 Hz), 4.08-4.00 (m, 2H), 3.73 (dq, 1H, J=15.4, 8.8 Hz), 2.57 (q, 1H, J=12.5 Hz), 2.36 (ddd, 1H, J=12.5, 6.6, 2.0 Hz), 1.07 (d, 3H, J=6.6 Hz).