Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([C:10](=O)[CH3:11])[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].Cl.[NH2:14]O.O.[OH-].[Na+]>CO>[CH3:11][C:10]1[C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[O:9][N:14]=1
Reactant: CCOC(=O)C(=O)C(Cl)C(C)=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A solution of ethyl 3-chloro-2,4-dioxovalerate (3.0 g, 15.6 mmol) and hydroxylamine hydrochloride (1.08 g, 15.6 mmol) in a mixuture of 1.5 mL of H2O and 1 mL of CH3OH was heated to reflux. After four hours TLC analysis indicated that all of the starting material had been consumed. Sodium hydroxide (0.31 g, 7.8 mmol) was added to the hot solution. After four hours the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in a 1:1 mixture to ethyl acetate/H2O. The aqueous layer was made basic with 2N NaOH and separated. The aqueous layer was then acidified with 2M HCl and extracted with ethyl acetate (125 mL). The ethyl acetate extract was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 600 mg (24% yield) of the desired product a gummy tan solid: 1H NMR (CDCl3) δ8.8 (bs, 1H), 2.3 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[C:7]([NH:25][C:26](=[O:28])[CH3:27])([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:26]([NH:25][C:7]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:33]1[O:34][C:35]([CH3:37])([CH3:36])[C:31]([CH3:38])([CH3:30])[O:32]1)[C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:29])(=[O:28])[CH3:27]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2-acetylamino-2-[4-(4-chlorophenyl)-cyclohexyl]hex-5-enoic acid tert-butylamide (940 mg, 2.25 mmol) in dichloromethane (9 mL) was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (45 mg, 3 mol %) and 1,2-bis(diphenylphosphino)ethane (54 mg, 6 mol %). After stirring for 30 minutes, 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (576 mg, 0.65 mL, 4.5 mmol) was added dropwise and the stirring was continued overnight. The reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10-40% ethyl acetate in heptane) gave 2-acetamido-N-tert-butyl-2-(4-(4-chlorophenyl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (985 mg, 80%); 1H NMR (CDCl3, 300 MHz) δ 7.25 (d, J=7.5 Hz, 2H), 7.08 (d, J=7.5 Hz, 2H), 6.99 (br s, NH, 1H), 5.52 (br s, NH, 1H), 2.84 (td, J1=13 Hz, J2=3.0 Hz, 1H), 2.37 (t, J=12 Hz, 1H), 2.24 (t, J=12 Hz, 1H), 2.00 (s, 3H), 1.90 (m, 4H), 1.20-1.48 (m, 7H), 1.38 (s, 9H), 1.22 (s, 12H), 1.06 (m, 2H) and 0.75 (t, J=7.5 Hz, 2H); MS (+CI): m/z for C30H48BClN2O4: expected 546.3. found 547.3 (M+H)+, 569.3 (M+Na)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([N:47]1[CH2:51][CH2:50][C@@H:49]([C:52](O)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:40]([N:47]1[CH2:51][CH2:50][C@@H:49]([C:52]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)[C@@H]1CCN(Cc2ccccc2)C1
Yield: 33.9 %

Procedure:
This compound was prepared according to method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.181 g; 0.476 mmol), (R)-1-benzylpyrrolidine-3-carboxylic acid hydrochloride (0.119 g; 0.476 mmol), and N,N-diisopropylethylamine (0.189 mL; 1.08 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of a solution of 5% ammonium hydroxide in methanol, in dichloromethane) to afford 0.056 g (34%) of (R)-1-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18](O)=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>CN(C=O)C>[CH2:40]([N:42]([CH2:43][CH3:44])[C:18](=[O:19])[C:11]1[CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]([O:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:13]([S:14]([NH2:17])(=[O:15])=[O:16])[CH:12]=1)[CH3:41]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CCNCC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 7, piretanide can be reacted with EDC, HOBt and diethylamine in DMF to yield N,N-diethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)-benzamide.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10].[CH3:22][O:23][CH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25]>C(Cl)Cl>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([NH:25][CH:24]([O:23][CH3:22])[C:26]([O:28][CH3:29])=[O:27])=[O:10])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)C(N)OC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.06 g, 0.05 mole) and p-nitrobenzyl chloroformate (10.78 g, 0.05 mole) are added to an ice-cold solution of methyl α-methoxyglycinate (6.10 g, 0.05 mole) in dry CH2Cl2 (100 ml). The resulting mixture is stirred in the cold and under N2 for 2 hours, and then washed with 3 portions of water. The CH2Cl2 phase is dried over MgSO4, filtered, and evaporated in vacuo. Recrystallization of the residue affords pure methyl N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycinate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=1.O[O:26][S:27]([O-:29])=O.[K+].[CH3:31]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:27]([CH3:31])(=[O:29])=[O:26])[N:18]=1
Reactant: CSc1nccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)n1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Product: CS(=O)(=O)c1nccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)n1
Reaction time: 8 h

Procedure:
To a RT slurry of 5-bromo-3-(2-(methylthio)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.855 g, 2.109 mmol) in MeOH (40 mL) was added oxone, monopersulfate compound (6.46 g, 10.51 mmol, Aldrich) and the reaction was stirred overnight. The reaction mixture was concentrated to ˜50% volume and diluted with water. The slurry was neutralized with 5 N NaOH and the solids were filtered, washed consecutively with water and MeOH, and dried in vacuo to give 795 mg of a light-yellow amorphous solid. m/z: 437.9, 439.0 [M+1].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[C:16](=[O:27])[CH:17]=[C:18]([C:24](O)=[O:25])[O:19]2)[CH3:9].P(Br)(Br)Br.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:24]([C:18]2[O:19][C:20]3[C:15]([C:16](=[O:27])[CH:17]=2)=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:8][CH3:9])[CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOCCOc1cccc2oc(C(=O)O)cc(=O)c12
Agent: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOCCOc1cccc2oc(C(=O)N3CCN(C)CC3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
1-methylpiperazine (4.5g.) was added dropwise to a suspension of 5-(2-ethoxyethoxy)chromone-2-carboxylic acid (5.0g.) in chloroform (50ml.). A solution of phosphorus tribromide (2.0g.) in chloroform (10ml.) was added dropwise to the resultant mixture under ice cooling for 10 minutes. The mixture was stirred under ice cooling for 2 hours and at room temperature for additional 1 hour, and then ethyl acetate (250ml.) was added to the reaction mixture. The mixture was washed twice with 5% aqueous solution of sodium bicarbonate and with water in turn, and dried. The solvent was distilled off under reduced pressure to give 2-(4-methyl-1-piperazinyl)carbonyl-5-(2-ethoxyethoxy) chromone (500mg.). The product was derived in the usual manner to its maleate.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>C1COCC1>[CH3:27][O:28][CH2:29][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.0 g, 4.07 mmol) in THF (20 mL) at −78° C. under nitrogen was added dropwise LDA (1.5 M in THF, 4.0 mL, 6.10 mmol). This solution was stirred for 1 hour at −78° C., after which methoxymethyl chloride (0.8 mL, 10.5 mmol) was added. The system was allowed to warm slowly to room temperature over 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate (3×50 mL). The organic layer was dried over a pad of silica gel, and the solvent removed under vacuum. The title compound was isolated by silica gel chromatography (5-10% ethyl acetate:hexanes) as a clear oil (830 mg, 69% yield). MS (ES+) [M+H]+=302.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:20]([CH3:23])[O:21][N:22]=3)[C:6](=[O:19])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:18])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:20]([CH3:23])[O:21][N:22]=3)[C:6](=[O:19])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](N)C1)c1cccc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](NC(=O)Nc3ccccc3)C1)c1cccc(Cl)c21

Procedure:
To the suspension of cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-amino-cyclohexane (0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH (0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121 mmol). After 20 min. the reaction was diluted with EtOAc, washed with water and concentrated to near dryness. After sonication and filtration a white solid (0.0412, 75%) was obtained.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)([OH:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:11][CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:24]=1)[OH:18])(=[O:33])[CH3:32]
Reactant: CN(C)CCOc1ccc(C(O)(c2ccccc2)C(CCO)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN(C)C)cc1
Temperature: 90 °C

Procedure:
The reaction is performed under dry conditions. 40.5 g of either (RR, SS)- or (RS, SR)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol and 150 ml of acetic acid anhydride are placed in a flask. The temperature is raised to 90° C., where it is kept until the primary OH-group is completely acetylated. [4-acetoxy-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butan-1-ol is obtained as intermediate; m.p. of the (RR, SS)-isomer pair is 97°-9° C⟧ While stirring the reaction mixture, 30 ml of acetyl chloride in 50 ml of acetic acid anhydride are added at 90° C. The stirring is continued at this temperature for 2 h. The solvent is evaporated. Then 1M sodium carbonate solution is added in excess, after which the product is extracted in toluene. The solution is dried over sodium sulfate, and the solvent is evaporated. The yield of the pure isomer mixture (Z:E 2:1) is quantitative. The m.p. of the (Z)-isomer is 67°-9° C. prepared from the corresponding (Z)-alcohol by refluxing in acetic acid.
Reaction SMILES: [Br:1][CH2:2][C@H:3]([CH3:11])[O:4]C1C[CH2:9][CH2:8][CH2:7][O:6]1.[Br:12]C[C@@H](O)C.O1C=CCCC1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[Br:1][CH2:2][C@@H:3]([OH:4])[CH3:11].[CH2:7]1[O:6][C@H:8]1[CH3:9].[BrH:12]
Reactant: C[C@@H](CBr)OC1CCCCO1
Agent: C1=COCCC1
Agent: C[C@H](O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Br
Product: C[C@H]1CO1

Procedure:
The manner in which optically active forms of arylmethoxy aliphatic amines, such as (2S)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine type compounds, are provided can vary. In one approach, a 3-aminobenzyl alcohol type compound (N-protected as the phthalimide) can be alkylated with a chiral 1-bromo-2-propanol type compound containing an O-protecting group, such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran using a base such as sodium hydride and a solvent such as N,N-dimethylformamide or tetrahydrofuran. The tetrahydropyranyl protecting group of the resulting chiral arylmethyl ether type compound can be removed with aqueous sulfuric acid in methanol, affording (2S)-1-[(3-aminophenyl)methoxy]-propan-2-ol. The resulting chiral alcohol intermediate can be converted to its corresponding tosylate, followed by tosylate displacement with methylamine with inversion of configuration, and finally removal of the N-phthaloyl group to give the chiral amine (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine. Chiral side chain compounds such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran can be prepared from (2S)-1-bromo-2-propanol by treatment with 3,4-dihydro-2H-pyran in dichloromethane with p-toluenesulfonic acid as a catalyst according to the method of S. A. M. Nieuwenhuis et al., Tetrahedron 50: 13207-13230 (1994). The required (2S)-1-bromo-2-propanol can be obtained from (S)-propylene oxide (commercially available from Fluka) by treatment with hydrogen bromide in acetic acid at 0° C. The corresponding optical antipode, (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine can be prepared in an analogous manner from (R)-propylene oxide (commercially available from Fluka) by using the synthetic procedure of S. A. M. Nieuwenhuis et al. to prepare the tetrahydropyranyl ether of (2R)-1-bromo-2-propanol and by using the synthetic sequence described above.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][C:19]=1[NH:27][C:28](=[O:31])[NH:29][NH2:30])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][C:19]=1[NH:27][C:28](=[O:31])[NH:29][N:30]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8])[CH3:16]
Reactant: CCOc1ccc(OCC)c(NC(=O)NN)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: CCOc1ccc(OCC)c(NC(=O)NN=c2c(=O)c3ccccc3c2=O)c1

Procedure:
ninhydrin, 4-(2,5-diethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[O:1]1[CH2:2][CH:3]([N:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:24](=[O:25])[C:23]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=2)[CH2:4]1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NC1COC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1COC1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from oxetan-3-yl-(4-o-tolyl-pyridin-3-yl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow solid (34%). MS (ESI): m/z=481.13 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[N+:3]=1[O-].CCOCC.CCCCCC>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Agent: [Fe]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(Br)c1
Temperature: 100 °C

Procedure:
To a solution of 2,6-dibromo-4-nitropyridine 1-oxide (6.80 g, 22.82 mmol) in acetic acid (100 mL) at rt was added Fe powder (6.40 g, 114.13 mmol). The resulting reaction mixture was heated to 100° C. for 1 h. After completion of reaction (by TLC), acetic acid was distilled off under reduced pressure, the residue was basified with aqueous ammonia solution and extracted with EtOAc (3×250 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was treated with ether and hexane and filtered to obtain the desired product as an off white solid (5.40 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:15][C:16]([NH:18][C@@:19]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]2[C@H:20]1[C@H:21]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17])([CH3:14])([CH3:13])[CH3:12]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)C.[Ag]=O>[C:11]([O:15][C:16]([NH:18][C@@:19]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:24]([O:25][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C@H:23]([OH:26])[C@@H:22]2[C@H:20]1[C@H:21]2[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1O
Agent: O=[Ag]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Add 3,4-dichlorobenzyl bromide (1.02 mL, 1.02 g, 4.26 mmol) to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3,4-dihydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (1.22 g, 2.84 mmol), tetra-n-butylammonium iodide (1.07 g, 2.84 mmol) and silver oxide (987.35 mg, 4.26 mmol) in dimethylformamide (17 mL) at room temperature. Stir overnight. Dilute with diethyl ether and hexanes (1:1), filter through celite, and then wash with ether and hexanes (1:1). The filtrate is washed with water, brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 0-30% ethyl acetate:hexanes to give the title compound (1.7 g, 2.84 mmol, 78%): MS (m/z): 610/612 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[ClH:1].[ClH:30].[ClH:1].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:20][CH2:21]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CCN(C)CC2)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCN(C)CC2)CC1
Product: Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(4-methylpiperazin-1-yl)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (53 mg, 0.13 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.152 mmol) followed by formation of the trihydrochloride salt to afford the desired product (11 mg, 14%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J=11.4, 2.2 Hz, 1H), 5.75-5.65 (m, 1H), 3.70 (br s, 8H), 3.10 (br s, 2H), 3.01 (s, 3H), 2.75 (s, 3H), 2.46-2.42 (m, 2H), 2.16-2.13 (m, 2H), 2.05-2.02 (m, 1H), 1.73-1.61 (m, 2H), 1.46-1.35 (m, 2H); ESI MS m/z 526 [M+H]+; HPLC>99% (AUC), tR=9.14 min.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][NH:5][CH:4]1[CH3:11].N1C=CC=CC=1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[OH:10][CH2:9][CH:7]1[CH2:6][NH:5][CH:4]([CH3:11])[CH:3]([O:2][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:8]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1NCC(CO)CC1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1NCC(CO)CC1OC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.9 g. of 3-hydroxy-5-hydroxymethyl-2-methylpiperidine hydrochloride in 10 ml. of pyridine was added to a solution of 0.9 g. of isonicotinoyl chloride hydrochloride in 25 ml. of dimethylformamide under cooling. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-water and extracted with chloroform. The extracted was washed with water, dried and the solvent was distilled off to give a crystalline substance. The substance was recrystallized from a mixture of ethyl acetate and hexane to give 0.7 g. of the desired product. m. p. 126° - 128°C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=S)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1.[NH3:17]>>[NH2:17][C:9]1[CH:8]2[CH2:13][CH2:14][CH2:15][CH:7]2[C:6]2[CH:5]=[C:4]([Cl:16])[CH:3]=[C:2]([Cl:1])[C:11]=2[N:10]=1
Reactant: S=C1Nc2c(Cl)cc(Cl)cc2C2CCCC12
Reactant: N
Product: NC1=Nc2c(Cl)cc(Cl)cc2C2CCCC12
Yield: 74 %

Procedure:
Analogously to Example 4, 6,8-dichloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (100 mg, 0.37 mmol) is reacted with 7N methanolic ammonia solution (20 ml) to form 70 mg (74%) of product.