Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:22][CH:23]=3)[N:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17]=2[O:40][C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=2[CH3:48])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:47][C:45]1[CH:44]=[CH:43][C:42]([CH3:48])=[C:41]([CH:46]=1)[O:40][C:17]1[N:18]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(OCC(=O)OC(C)(C)C)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccc(OCC(=O)O)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
The compound of step 1 (88 mg, 133 μmol) was dissolved in DCM (20 ml), TFA (5 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the obtained solid was purified by preparative HPLC. The eluate was lyophilized overnight. The residue was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 45 mg of the title compound were obtained in the form of the [2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indol-6-yloxy]-acetic acid hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>C(O)C>[CH3:19][C:17]1[N:16]=[C:15]([S:20][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:14]=[C:13]([NH2:12])[CH:18]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cc(N)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
In a 100 mL round bottom flask, 2-(bromomethyl)-1,3,4-trichlorobenzene (550 mg, 2.0 mmol), 4-amino-6-methylpyrimidine-2-thiol (282 mg, 2.0 mmol), and triethylamine (0.28 mL, 2.0 mmol) were mixed in ethanol (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. To the crude solid, water (50 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide a white solid (530 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.65 (s, 2H), 6.03 (s, 1H), 6.90 (br, 1H), 7.55 (d, 1H), 7.64 (d, 1H); M+334, 336.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH3:6][C:7]1([CH3:15])[C:12](=O)[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8]1.C([BH3-])#[N:17].[Na+]>CO>[NH2:17][CH:12]1[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8][C:7]1([CH3:15])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CC1CNCC(C)(C)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CNCC(C)(C)C1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 3,3,5-trimethyl-4-piperidone (0.8 g, 5.67 mmol) in methanol (20 ml) and stirring was continued for 3 hr at temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.25 g, 3.96 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-3,3,5-trimethylpiperidine. Yield 0.45 g (54%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:17]1[CH:22]=NC2N(O)N=[N:25][C:19]=2[CH:18]=1.CCN(C(C)C)C(C)C.C1(N)CCC1>CN(C=O)C.C(Cl)CCl>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:25][CH:19]1[CH2:18][CH2:17][CH2:22]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)NC1CCC1
Reaction time: 2 h

Procedure:
To a solution of 4.98 g N-Boc-cis-4-hydroxy-L-proline in 50 ml DMF were added 4.13 g EDC, 2.93 g HOAt, 3.75 ml DIPEA and 1.53 g cyclobutylamine at 0° C. After stirring for 2 h the reaction mixture was concentrated, the residue was dissolved in ethyl acetate and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation. Yield: 3.32 g colorless amorphous solid.
Reaction SMILES: FC(F)(F)C1C=C(C(F)(F)F)C(C(N)=O)=CC=1.[NH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24][C:25](=[O:40])[C:26]1[C:31]([S:32][CH3:33])=[CH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[CH:28][C:27]=1[O:38][CH3:39].[I-].C([N+]1(C)[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)C>>[CH3:39][O:38][C:27]1[CH:28]=[C:29]([C:34]([F:36])([F:37])[F:35])[CH:30]=[C:31]([S:32][CH3:33])[C:26]=1[C:25]([NH:24][CH:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[N:18]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:40]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: NC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [I-]
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(=O)CC1

Procedure:
The title compound, yellow gum, MS: m/e=431.3 [(M+H)+], was prepared in accordance with the general method of intermediate J from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([CH2:20][N+:21]([O-:23])=[O:22])[CH2:14][C:15](OCC)=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([CH2:20][N+:21]([O-:23])=[O:22])[CH2:14][CH2:15][OH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)C[C@H](C[N+](=O)[O-])[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](CCO)C[N+](=O)[O-]

Procedure:
A 7.5 g sample of ethyl 3-(R)-(1-BOC-2-(S)-pyrrolidinyl)-4-nitrobutanoate (prepared according to the procedure of Hayakawa et al., U.S. Pat. No. 5,098,912, issued Mar. 24, 1992) was dissolved in 35 mL of ether and treated with 0.76 g of LAH. After careful quenching of the excess reagents, the title compound was extracted and purified by chromatography (4.5 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C@@:9]12[CH2:14][CH:13]1[CH2:12][NH:11][C@H:10]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][N:31]([CH2:33][C:34]1[NH:38][N:37]=[N:36][C:35]=1[CH:39]=O)[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]12[CH2:14][CH:13]1[CH2:12][N:11]([CH2:39][C:35]1[N:36]=[N:37][NH:38][C:34]=1[CH2:33][N:31]([CH3:32])[CH3:30])[CH:10]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)Cc1[nH]nnc1C=O
Reactant: FC(F)(F)c1cc(COC[C@@]23CC2CN[C@H]3c2ccccc2)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: COCCOC
Product: CN(C)Cc1[nH]nnc1CN1CC2CC2(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To racemic Intermediate 24, one enantiomer being (1S,2S)-1-(3,5-bis-trifluoromethyl-benzyloxymethyl)-2-phenyl-3-aza-bicyclo[3.1.0]hexane (0.08 g, 0.18 mmol) in DME (1.0 mL) was added 5-dimethylaminomethyl-1H-[1,2,3]triazole-4-carbaldehyde (˜50% pure, 0.14 g, 0.91 mmol) and the mixture stirred at room temperature for 3 hours. To the reaction flask was added sodium triacetoxyborohydride (0.08 g, 0.36 mmol) and stirring was continued for 16 hours. To the reaction flask was added 1 N HCl (2 mL) and the mixture stirred for 2 hours. 1 N NaOH solution was added cautiously and then saturated sodium bicarbonate solution was added until the pH=8. The reaction mixture was extracted with methylene chloride, the organics washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using elution of a gradient of 50% EtOAc/Hexanes to 3% MeOH/EtOAc to give the title compound. (0.065 g, 66% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxybenzaldehyde (19.3 g) and benzyl bromide (25.9 g) were dissolved in N,N-dimethylformamide (50 mL). Cesium carbonate (59.0 g) was added to the solution at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2-benzyloxybenzaldehyde. This compound was dissolved in methanol (100 mL). Sodium borohydride (5.73 g) was added to the solution at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether, and the organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (32.4 g).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:37]N)=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([N:37]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1
Reactant: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4cc(Cl)ccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-31) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=499.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([NH:30]C(=O)C(F)(F)F)=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)=[O:17])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:3].CO.[OH-].[Na+]>O1CCCC1>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]([NH:15][C:10]3[CH:9]=[CH:8][C:7]4[CH2:6][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:14][CH2:13][C:12]=4[CH:11]=3)=[O:17])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1
Reactant: CN(C)CC1CCc2cc(NC(=O)c3ccc(-c4ccc(NC(=O)C(F)(F)F)cc4)cc3)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC1CCc2cc(NC(=O)c3ccc(-c4ccc(N)cc4)cc3)ccc2C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
N-[6-[(N,N-Dimethylamino)methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-[(trifluoroacetyl)amino][1,1′-biphenyl]-4-carboxamide (850 mg, 1.72 mmol) obtained in Example 31 was suspended in a mixed solution of methanol (8 ml) and tetrahydrofuran (4 ml), then 1N sodium hydroxide (3.4 ml) was added, which was stirred at 50° C. for 16 hours. The solvent was distilled out under reduced pressure, and the residue was pulverized using water, to give the titled compound (685 mg) as a white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:20]2[C:11](=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=3)[N:10]([CH2:23][C:24]([NH:26][CH3:27])=O)[N:9]=1>O1CCCC1>[CH3:27][NH:26][CH2:24][CH2:23][N:10]1[C:11]2=[N:12][C:13]3[C:18]([CH:19]=[C:20]2[C:8]([NH2:7])=[N:9]1)=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=3
Reactant: CNC(=O)Cn1nc(N)c2cc3cc(OC)ccc3nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCn1nc(N)c2cc3cc(OC)ccc3nc21
Temperature: 0 °C
Yield: 14.7 %

Procedure:
To a suspension of 2.00 lithium aluminum hydride in 100 ml tetrahydrofuran was added, portionwise, 5.5 g 3-amino-6-methoxy-N-methyl-1H-pyrazolo[3,4-b]quinolin-1-acetamide (Example 26) and 50 ml of tetrahydrofuran. The mixture was heated at reflux for 4 hours, then cooled and poured into ice-water. The solid product was collected and chromatographed on silica gel using 95% chloroform/5% isopropylamine as eluant. The fractions were combined and evaporated, and the product recrystallized from ether/hexane to give 0.77 g 1-[2-(methylamino)ethyl]-6-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine, orange solid, m.p. 142°-144° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([CH3:23])([O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:11])=O)(C)(C)C.C1(OC)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][C:10]([CH3:23])([O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:11]
Reactant: COC(=O)c1ccc(OC(C)(C)CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(C)(C)CN)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.7 %

Procedure:
A mixture of methyl 4-(1-tert-butoxycarbonylamino-2-methyl-2-propoxy)benzoate (460 mg, 1.42 mmol) and anisole (0.155 mL, 1.42 mmol) in CH2Cl2(15 mL) and TFA (3 mL) was stirred for 3 hr at room temp. The mixture was evaporated off. The residue was dissolved in CH2Cl2 (30 mL) and made basic by the addition of 0.5 N NaOH. The CH2Cl2 layer was separated, dried over Na2SO4, and evaporated. The residue was chromatographed on silica-gel with CH2Cl2 as eluent to give 370 mg (100%) methyl 4-(1-amino-2-methyl-2-propoxy)benzoate as a gum. 1H-NMR (CDCl3) δ 1.34 (s, 6H), 2.87 (s, 2H), 3.90 (s, 3H), 7.10 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H).
Reaction SMILES: [F:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[C:19]([O:21]C)=[O:20].[ClH:35]>C(OC(C)C)(C)C>[ClH:35].[ClH:35].[F:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(F)c1ccnc2ccc(OC)cc12
Agent: Cl
Solvent: CC(C)OC(C)C
Product: COc1ccc2nccc(C(F)CC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
A solution of 0.2 g of methyl (3R,4R)-4-[3-(R,S)-fluoro-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate in 3 cm3 of 6N aqueous hydrochloric acid was heated with stirring at a temperature in the region of 100° C. for 7 hours and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The residue obtained was stirred in 10 cm3 of diisopropyl ether. The crystals which resulted therefrom were filtered off, washed with 2 times 5 cm3 of diisopropyl ether, and dried under reduced pressure (13 Pa) at a temperature in the region of 60° C. 0.22 g of (3R,4R)-4-[3-(R,S)-fluoro-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride were obtained in the form of a solid with a beige color melting with softening at a temperature in the region of 140° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:19]2[N:18]([C:20]3[C:28](C)=[C:27]([C:30]([O-])=[O:31])[C:26]([O:33][CH2:34][CH:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][CH3:39])=[C:25](C)[C:21]=3[C:22]([O-])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C1COCC1>[CH:16]1[C:17]2[N:18]([C:20]3[CH:28]=[C:27]([CH2:30][OH:31])[C:26]([O:33][CH2:34][CH:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:25][C:21]=3[CH2:22][OH:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCCCC(CC)COc1c(C)c(C(=O)[O-])c(-n2c3ccccc3c3ccccc32)c(C)c1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)COc1cc(CO)c(-n2c3ccccc3c3ccccc32)cc1CO
Temperature: 25 °C
Yield: 97 %

Procedure:
300 ml of absolute THF and 0.94 g (2.5×10−2 mol) of LiAlH4 were introduced into a three-neck flask. While stirring the flask, 4 g (8.2×10−3 mol) of 2-(N-carbazolyl)-5-(2′-ethylhexyloxy)-dimethylterephthalate prepared in the above step (6) in 150 ml of THF was slowly added thereto. After being refluxed for 4 hours, the reaction solution was cooled to room temperature and combined with 0.9 ml of water, 0.9 ml of 15% NaOH and 2.7 ml of water, in order. The precipitate so formed was filtered off and the solvent was distilled off under reduced pressure, to obtain the title compound as white solids. M.p.: 128° C.; yield: 97% (3.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:9]([C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:13])=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1ccc(F)cc1F
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(F)cc1F)c1cc([N+](=O)[O-])ccc1O
Yield: 32.4 %

Procedure:
A solution of 5-nitrosalicylic acid (1.4 g, 7.7 mmol) and 2,4-difluoroaniline (0.8 mL, 7.7 mmol) in chlorobenzene (40 mL) was treated with PCl3 (0.338 mL, 3.8 mmol). The solution was heated at reflux under an argon atmosphere. After 2 h. the solution was filtered hot and the filtrate was left standing at RT. After 18 h the solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.733 g, 35% yield): 1H NMR (400 MHz, DMSO-d6) δ 2.5-2.6 (s, 3H), 7.1-8.9 (m, 6H), 10.6-10.7 (s, 1H)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1CCOC[CH2:18]1.C[O-].[Na+].CO>O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:17][CH3:18])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: C1COCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 93 %

Procedure:
To a round bottom flask was added 2-benzyl-4,5-dichloropyridazin-3(2H)-one (7.14 gm, 27.99 mmol), dioxane (125 ml, anhydrous). To the resulting reaction mixture was slowly added 25%/NaOMe in MeOH solution (6.98 ml, 30.51 mmol). The reaction was stirred at rt for 70 min. After this time, the reaction mixture was diluted with water (200 ml). The resulting solution was poured into a separatory funnel and extracted with CH2Cl2 (2×100 ml). The combined organic layers were washed with saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with 0-5% MeOH/CH2Cl2 to give product 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one as colorless oil (6.5 gm, 93% yield). HPLC retention time (method A) 3.090 min; LCMS (M+H)=251.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.[Li]C(C)(C)C.C(=O)=O.[C:20](OC)(=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:25]
Reactant: COC(=O)C(=O)OC
Reactant: Cn1ccc2cccc(Br)c21
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1cccc2ccn(C)c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
A solution of 1-methyl-7-bromoindole (1.53 g, 7.29 mmol) in THF (50 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentanes (10 mL, 17 mmol) added dropwise over 10 min. After 15 min, the resultant bright yellow suspension was transferred over 15 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (2.13 g., 18.1 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The cloudy yellow mixture was treated with pH 7.0 buffer, poured into EtOAc and the EtOAc washed with pH 7.0 buffer, saturated aq NaHCO3, brine, dried (MgSO4) and concentrated to a cloudy oil. Flash chromatography (10% EtOAc/hexanes) afforded the title compound (896 mg, 57%) as a bright yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.97 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.48 (d, J=3 Hz, 1H), 7.20 (dd, J=8 Hz, 1H), 6.66 (d, J=3 Hz, 1H), 3.95 (s, 3H), 3.79 (s, 3H). 13C (75.5 MHz, DMSO-d6) 185.80, 164.31, 133.64, 133.02, 131.23, 128.07, 127.04, 118.77, 118.25, 102.15, 53.01, 37.49. IR (CHCl3, cm−1) 1739, 1678. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.48; H, 5.23; N, 6.51.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[O:28].CN1CCOCC1>ClCCCl>[CH:10]1([N:9]2[C:4]3([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:3][O:28][C:27]2=[N:26][C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: ClCC1(NC2CCCCC2)CCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCCCC1
Temperature: 50 °C
Yield: 1.4 %

Procedure:
To a solution of 1-(chloromethyl)-1-(cyclohexylamino)cyclopentane HCl salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 mmol) in 1,2-dichloroethane (10 mL) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated to 50° C. for 18 h, then cooled to 20° C. and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to yield 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane (0.021 g, 1.4%): CI-MS m/z 358 ((M+H)+).