Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[NH:5]([C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:8][CH:7]=1)[C:1]([CH3:2])=[O:3]
Reactant: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(OC2(c3ccccc3)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.85 g of acetyl chloride in 5 ml of benzene is added dropwise to a solution of 2.8 g of 4-(4-aminophenoxy)-1-methyl-4-phenylpiperidine and 1.1 g of triethylamine in 10 ml of benzene. After stirring the mixture at room temperature for 6 hours, it is concentrated; the resulting residue is taken up with 30 ml each of water and diethyl ether; the obtained mixture is shaken thoroughly, and the organic phase is separated off, dried over sodium sulfate and concentrated. 2.8 g of the title compound remain as a viscous yellow oil which crystallizes (m.p. 143° to 144° C.) from diethylether after standing for several days.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:14]=1)=O)(C)(C)C.CC(O)=O.[ClH:27].O1CCOCC1>CCO.[Pt]>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:14]=[C:15]([S:19]([NH2:20])(=[O:21])=[O:22])[CH:16]=[CH:17][CH:18]=1.[ClH:27]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc(S(N)(=O)=O)c1
Agent: [Pt]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(C2CCCN2)c1

Procedure:
3B (290 mg, 0.9 mmol) was hydrogenated in EtOH (9.0 mL) and HOAc (0.15 mL) with Pt/C (5% wt, 100 mg) using a H2 balloon for 2 days. After filtration and evaporation of solvent, the crude product was stirred in EtOAc (1.0 mL) and 4.0 N HCl/dioxane (4.3 mL, 18 eq) at rt for 1.0 h. After removal of solvent, 3C was obtained as HCl salt. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.26 (m, 3H) 2.55 (m, 1H) 3.49 (m, 2H) 4.74 (dd, J=10.11, 6.59 Hz, 1H) 7.66 (t, J=7.69 Hz, 1H) 7.74 (m, 1H) 7.97 (d, J=7.91 Hz, 1H) 8.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:18]=1[CH3:26]>O1CCCC1.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:12][C:5]3[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=3[C:3]=2[C:13]([NH2:15])=[O:14])=[CH:19][C:18]=1[CH3:26]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Reactant: Cc1cc(N=C=O)ccc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)c(C)c3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a stirred solution of compound F4 (450 mg, 2.00 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature under nitrogen was added a solution of compound F2 (402 mg, 2.40 mmol) in anhydrous methylene chloride (6 mL) dropwise over 3 min. Then the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered. The filter cake was washed with methylene chloride (5 mL) and then dried under reduced pressure to provide compound F5 as a white solid (301 mg, 38%): 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.12 (s, 1H), 7.48-6.75 (m, 5H), 3.45 (s, 2H), 2.77 (d, J=4.8 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H), 2.55-2.45 (m, 2H), 2.30 (s, 3H), 1.07 (t, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)(C)C>[CH2:20]([NH:27][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Nc2cc(C3CC3)[nH]n2)c2occc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: c1ccc(CNc2nc(Nc3cc(C4CC4)[nH]n3)c3occc3n2)cc1
Temperature: 100 °C
Yield: 5.1 %

Procedure:
To a vial was added 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine (0.20 g, 0.73 mmol), benzyl amine (0.79 mL, 7.3 mmol), X-Phos (0.02 g, 0.04 mmol) K2CO3 (0.50 g, 3.6 mmol), and Pd2dba3 (0.04 g, 0.04 mmol). To the vial was added t-BuOH (3.6 mL) and tube was sealed. The tube was evacuated, purged with nitrogen three times and stirred over night at about 100° C. To the mixture was added additional benzyl amine (0.79 mL, 7.3 mmol), X-Phos (0.02 g, 0.04 mmol), and Pd2dba3 (0.04 g, 0.04 mmol). The mixture was stirred at about 100° C. for about 26 h. The mixture was filtered, the filter pad was washed with DCM and then the solvent was removed in vacuo. The crude material was added to a silica gel column and was eluted with EtOAc/DCM (50% to 100% gradient) followed by 2.0 M NH3 in EtOH/DCM (2%) to give N2-benzyl-N4-(5-cyclopropyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidine-2,4-diamine (0.013 g, 5%). LC/MS Rt=1.30 min; MS m/z 347.29 (M+H)+. Syk IC50=B.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH:13]=O)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1.[F:23][CH:24]1[CH2:27][NH:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH2:13][N:26]3[CH2:27][CH:24]([F:23])[CH2:25]3)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1
Reactant: O=CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: FC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc2c1cc1n2C(CCN2CC(F)C2)Cc2ccc(Cl)nc2-1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A mixture of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetaldehyde (200 mg, 0.617 mmol) and 3-fluoroazetidine (95 mg, 1.23 mmol) in DCM (4 mL) was stirred at room temperature for 30 minutes under N2. Then Na(OAc)3BH (50 mg) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. After dilution with water (30 mL) and extraction with EA (20 mL×3), the organic layer was washed with brine (30 mL*3), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=1:1) to afford the desired product of 2-chloro-11-fluoro-6-(2-(3-fluoroazetidin-1-yl)ethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (100 mg, yield: 43%). 1H-NMR (CDCl3, 400 MHz) δ 7.44 (d, J=8.0 Hz, 1H), 7.3 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.10 (t, J=4.8 Hz, J=2.7 Hz, 2H), 6.69˜6.74 (m, 1H), 5.11˜5.14 (m, 0.5H), 4.97˜4.50 (m, 0.5H), 4.87 (t, J=4.8 Hz, 1H), 3.57 (d, J=6.8 Hz, 1H), 3.33˜3.39 (m, 1H), 2.95˜3.06 (m, 2H), 2.2˜72.38 (m, 1H). MS (M+H)+: 374/376.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:22]([Cl:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([Cl:23])[C:14]([Cl:13])=[CH:15][C:16]=2[O:24][CH3:25])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(Cl)c(Cl)cc1C(=O)O
Product: COc1cc(Cl)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4,5-dichloro-2-methoxybenzoic acid
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[O:15]1[CH2:39][CH:16]1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([CH:28]2[CH2:33][CH2:32][CH:31]([O:34][CH2:35][CH:36]3[O:38][CH2:37]3)[CH2:30][CH2:29]2)([CH3:27])[CH3:26])[CH2:21][CH2:20]1>>[OH:15][CH:16]([CH2:39][N:11]1[C:10]([CH3:13])([CH3:12])[CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3][C:2]1([CH3:14])[CH3:1])[CH2:17][O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([CH:28]2[CH2:29][CH2:30][CH:31]([O:34][CH2:35][CH:36]([OH:38])[CH2:37][N:11]3[C:2]([CH3:14])([CH3:1])[CH2:3][C:4]4([O:5][CH2:6][CH2:7][O:8]4)[CH2:9][C:10]3([CH3:13])[CH3:12])[CH2:32][CH2:33]2)([CH3:27])[CH3:26])[CH2:23][CH2:24]1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Reactant: CC(C)(C1CCC(OCC2CO2)CC1)C1CCC(OCC2CO2)CC1
Product: CC(C)(C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1)C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1
Temperature: 120 °C

Procedure:
A mixture of 8.8 g of 7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane and 7.0 g of 2,2-bis[4-(2,3-epoxypropoxy)cyclohexyl]propane was heated at 120° C. for 30 hours. After completion of the reaction, the reaction mixture was purified by column chromatography through silica gel eluted with ethyl acetate. The desired Compound No. 207 was obtained in the form of a pale yellow oil which after being kept at ambient temperature, turned to a solid melting at 48°-50° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].[C:23]([CH2:27][O:28][CH2:29][CH2:30]Br)([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:18][CH2:19][N:20]([CH2:30][CH2:29][O:28][CH2:27][C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]1)=[O:16]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COC(=O)COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(C(=O)C2CCN(CCOCC(=O)OC)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix 1-[[(2-ethoxy)ethyl]-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (3.89 g, 12.91 mmol), carbomethoxy methoxy ethylbromide (3.01 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo to give and purify by chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:17])=[C:7]([C:11]([I:16])=[C:12]([NH2:15])[C:13]=1[I:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[C:18]1(=[O:25])[O:24][C:22](=O)[CH2:21][CH2:20][CH2:19]1.S(=O)(=O)(O)O>O>[C:22]1(=[O:24])[N:15]([C:12]2[C:11]([I:16])=[C:7]([C:6]([I:17])=[C:5]([N:4]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:2][C:1]3=[O:3])[C:13]=2[I:14])[C:8]([OH:10])=[O:9])[C:18](=[O:25])[CH2:19][CH2:20][CH2:21]1
Reactant: O=C1CCCC(=O)O1
Reactant: CC(=O)Nc1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(I)c(N2C(=O)CCCC2=O)c(I)c(N2C(=O)CCCC2=O)c1I

Procedure:
From 3-acetamido-5-amino-2,4,6-triiodobenzoic acid. A mixture of 11.4 g. of 3-acetamido-5-amino-2,4,6-triiodobenzoic acid, 23 g. of glutaric anhydride and 1 ml. of concentrated sulfuric acid was heated on a steam bath for 21/2 hours. The reaction mixture was stirred with water and the product (14.4 g.) collected by filtration. The product was recrystallized twice from acetone to give 3,5-bis(glutarimido)-2,4,6-triiodobenzoic acid. The same compound is obtained if the 3-acetamido-5-amino-2,4,6-triiodobenzoic acid is replaced by 3,5-diacetamido-2,4,6-triiodobenzoic acid.
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:36].[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:44])[NH2:27])=[CH:24][CH:25]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 80 %

Procedure:
Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 80% of theory, C28H28N4O3S (500.62) Rf value: 0.30 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =501
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])[O:11][C@@H:10]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:9]1)(=O)C>CO>[C:15]([CH:14]=[CH:13][C@H:12]1[O:11][C@@H:10]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:9][C@@H:8]1[OH:7])([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
About 10 drops of a 25% sodium methoxide in methanol were added to a stirred solution of 1.5 g of 3'-O-acetyl-5'-carbomethoxymethylene-5'-deoxythymidine in 150 ml of dry methanol (passed through a bed of neutral alumina). The mixture was stirred at room temperature under a nitrogen atmosphere for an additional 6 hours.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C=O)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 99.7 %

Procedure:
To a stirred solution of methyl 4-chloro-3-nitrobenzoate T10.1 (10.00 g, 46 mmol) (commercially available from Aldrich) in DMF (15.00 mL, 194 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (12 g, 70 mmol) (commercially available from Aldrich), and potassium carbonate (19 g, 139 mmol). Tetrakis(triphenylphosphine)palladium (2.1 g, 1.9 mmol) was then added to the mixture, and the mixture was heated at 90° C. for 18 hours. The mixture was then cooled to room temperature, diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-40% EtOAc in hexanes) to yield T10.2 as a colorless oil (14.00 g, 99% yield).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:9][CH2:10]Cl)[CH2:6][CH2:7]Cl.[CH2:12]([O:14][CH2:15][CH2:16][OH:17])[CH3:13]>>[CH2:4]([N:5]([CH2:9][CH2:10][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[CH2:6][CH2:7][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[CH2:3][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13]
Reactant: CCOCCO
Reactant: ClCCN(CCCl)CCCl
Agent: Cl
Product: CCOCCOCCN(CCOCCOCC)CCOCCOCC
Yield: 68 %

Procedure:
51.6 g (i.e., 0.215 mol) of tris-(2-chloroethyl)-amine hydrochloride were added to the above mixture (a). The mixture was subsequently heated at the reflux temperature of the 2-ethoxyethanol for 12 hours and the solvent was then distilled under reduced pressure. The excess sodium 2-ethoxyethanolate was neutralized by adding 12 cm3 of aqueous HCl (10 N) thereto. The sodium chloride was filtered off and the solution was distilled. The tris-(3,6-dioxaoctyl)-amine distilled between 200° C. and 210° C. under a pressure of 1 mm Hg. The yield was 68%.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[S:19][CH:20]=2)[CH:14]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]=[O:22])[S:19][CH:20]=2)[CH:14]=1
Reactant: O=C(Nc1cnn(Cc2csc(CO)n2)c1)OCc1ccccc1Cl
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-hydroxymethyl-thiazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (230 mg, 0.61 mmol) in AcCN (6.0 mL) was treated at rt with MnO2 (293 mg, 3.04 mmol). The reaction mixture was stirred at rt overnight before being filtered through Celite and the solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.96 min; [M+H]+=377.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:11][CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:25][CH2:26]3)[C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1
Reactant: CCCCc1ccc(F)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 5 parts of 1-chloro-4,4-bis(p-fluorophenyl-butane 3.8 parts of 5-chloro-1-(4-piperidyl)-2-benzimidazolinone, 1.4 parts of sodium bicarbonate and 80 parts of absolute ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated. Water and toluene are added to the residue and the whole is shaken vigorously. The layers are separated and the toluene layer is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is triturated in diisopropylether. The solid product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 5-chloro-1{1-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl}-2-benzimidazolinone; mp. 185.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:3]=12.[OH2:16]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:16])=[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:3]=12
Reactant: Cc1ccnc2c1C(=O)c1ccccc1-2
Reactant: O
Solvent: ClC(Cl)Cl
Product: Cc1cc[n+]([O-])c2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
A solution of 12.7 g (0.065 mol) of 4-methyl-5H-indeno[3,2-b]-pyridin-5-one in 550 ml of chloroform was added dropwise at 25° C. to a solution of 13 g (0.066 mol) of water-moist 3-chloroperbenzoic acid in 500 ml of chloroform. After stirring at room temperature for 12 hours, the mixture was washed twice with 50 ml each of a saturated aqueous sodium hydrogen carbonate solution and then with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was crystallized at 0° C. using 20 ml of diethyl ether. 12.4 g (90.5% of theory) of 4-methyl-5H-indeno[3,2-b]pyridin-5-one-N-oxide were obtained as white crystals of m.p. 218°-220° C.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:17])[CH3:16]
Reactant: CCOC(=O)CCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid mohohydrate gives a yellow oil, b.p. 98°-103° C. (0.35 mm).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[CH3:28][C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][C:29]([OH:35])([CH3:28])[CH2:30][CH2:31]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: CC1(O)CCNCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-methyl-piperidin-4-ol and pyridine in chloroform. [α]D20=+25.2° (c=1.07, CHCl3), ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl-].[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([C:23]([C:22]3[CH:26]=[CH:27][C:19]([C:18]([O:17][CH3:16])=[O:28])=[CH:20][CH:21]=3)=[O:24])[CH:9]=[CH:10][C:11]1=2
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 0 °C
Yield: 104.5 %

Procedure:
1,2,3,4-Tetrahydro-1,1,4,4-tetramethylnaphthalene (10.0 g, 53.2 mmol) and terephthalic acid monomethyl ester chloride (10.0 g, 50.5 mmol) were dissolved in dichloromethane (50 ml) and the mixture was added with AlCl3 (14.3 g, 107.5 mmol) over 10 minutes under ice cooling. After reflux for 1 hour, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried, and then concentrated to give methyl 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoate (Compound 43, 18.5 g, 99%). A part of the product was recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (t, J=7.2 Hz, 3H).