Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:11][CH2:10]2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[NH2:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:11][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)ccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Yield: 100 %

Procedure:
A mixture of 21.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 20 parts (100%) of 1-[3-{4-[(2-amino-4-chlorophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 17.5 g (0.128 mol) of zinc chloride, 54 ml of ethyl acetate and 2.5 g of concentrated hydrochloric acid, 46.1 g (0.153 mol) of isophytol (purity: 98.3%) was added dropwise under stirring at 25-30° over 3 hours. At the same temperature, the reaction mixture was stirred for an additional 2 hours. After the reaction mixture was washed with 10 ml of water, the solvent was distilled off. Toluene (100 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 66.0 g of the title compound was obtained as a brown oil (yield: 95.2%, GLC purity: 95.1%, α-tocopheryl acetate content: 2.0%, ethyl acetate recovery rate: 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:18]2[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:19]2)[C:4](=[O:8])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=c1cc(Br)cc[nH]1
Product: CC(C)(C)OC(=O)N1CC(n2ccc(Br)cc2=O)C1

Procedure:
The title compound was prepared from 4-bromopyridin-2(1H)-one and 3-iodo-azetidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 22.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[Br:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ncc(Br)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(Br)s1
Reaction time: 3 h

Procedure:
2-Amino-5-bromothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture was cooled and filtered to recover the desired product 5-bromothiazol-2-yl isocyanate dimer as a fine yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][C:14]=2[O:27]CC2C=CC=CC=2)(O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(O)cc2O)C1
Reaction time: 24 h
Yield: 27.8 %

Procedure:
1 g of 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester are dissolved in a mixture of 20 ml of ethyl acetate/10 ml of methanol, and then 0.2 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 24 hours under a hydrogen atmosphere. The reaction mixture is filtered and then the residue is chromatographed on silica gel (7/3 heptane/ethyl acetate). 0.16 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester is obtained. Yield=28%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH3:24])[CH:16]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]2=[O:25])=[CH:16][C:17]=1[CH3:24]
Reactant: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1N
Yield: 94.1 %

Procedure:
A solution of 4-(benzyloxy)-1-(3-methyl-4-nitrophenyl)pyridin-2(1H)-one (0.940 mg, 2.79 mmol) in EtOH (19.2 mL) and H2O (4.8 mL) was treated with iron powder (1.35 g, 24.2 mmol) and NH4Cl (64.1 mg). After stirring at reflux for two hours, the reaction mixture was filtered through Celite and the filtrate concentrated to yield the title compound (0.804 g, 94%) as an off-white solid 1H NMR (500 MHz, DMSO-d6) δ 7.45-7.34 (m, 6H), 6.85 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.00 (dd, J=7.5, 5.0 Hz, 1H), 5.90 (d, J=2.0 Hz, 1H), 5.11 (s, 2H), 5.03 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[C:9]1([N:15]2[C:19]3[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[S:22][CH2:23][C:18]=3[C:17]([C:28](Cl)=[O:29])=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C)C=O.O1CCOCC1>[C:1]([CH:3]([C:28]([C:17]1[C:18]2[CH2:23][S:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19]=2[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:16]=1)=[O:29])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: N#CCC(N)=O
Reactant: O=C(Cl)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#CC(C(N)=O)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Temperature: 25 °C

Procedure:
2-Cyanoacetamide (1.85 g) is treated with 50% sodium hydride (1.28 g) in dimethylformamide (35 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride (6.53 g), prepared according to Example 15, dissolved in dioxane (35 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 2 hours, then is diluted with ice water and acidified to pH 1 with 37% HCl. The gummy precipitate is extracted with ethyl acetate and the organic solution washed with N HCl and then evaporated to dryness in vacuo. The residue is purified over SiO2 column, using chloroform/methanol 80:20 as eluent, to give 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide, m.p. >300° C. dec., NMR (DMSO d6) δ ppm: 4.10 (s) (2H, --S--CH2 --), 6.00-7.00 (bs) (2H, CONH2), 6.60-7.80 (m) (9H, phenyl protons), 9.00 (bs) (1H, OH).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[NH2:13][C:14]1[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:13]1[C:14]1[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1

Procedure:
1,3-Dioxo-2-(2,6-dimethoxypyridin-3-yl)-isoindoline (5) was prepared and isolated as follows. A mixture of phthalic anhydride (0.89 g, 6 mmol), 3-amino-2,6-dimethoxypyridine monohydrochloride (95%, 1 g, 5 mmol) and sodium acetate (0.49 g, 6 mmol) in glacial acetic acid (50 ml) was refluxed for 3 h. The solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 ml) and washed with water (100 ml×3), dried over Na2SO4 and concentrated to give the crude product. The crude product was recrystallized with ethyl acetate to give 5 (1.345 g, 90%) as a pale pink crystals: nip 182-183° C.; 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.80-7.76 (m, 2H), 7.44 (d, J=8.1 Hz, 1H), 6.42 (d, J=8.1 Hz, 1H, 3.95 (s, 3H), 3.91 (s, 3H); 13C NMR (DMSO-d6) δ 166.5, 160.6, 156.1, 140.1, 132.8, 129.4, 121.4, 104.6, 99.3, 51.7, 51.5; MS (CI/CH4) 285 [M+1]+. Anal. Calcd for C15H12N2O4: C, 63.38; H, 4.25; N, 9.85. Found: C, 63.57; H, 4.18; N, 9.65.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([OH:17])[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:6][NH:7][CH2:9][CH:10]([OH:17])[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(CC(O)CN1CCCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCC(O)CN1CCCC1

Procedure:
1-Methylamino-3-pyrrolidin-1-yl-propan-2-ol was prepared from (2-Hydroxy-3-pyrrolidin-1-yl-propyl)-methyl-carbamic acid tert-butyl ester following General Procedure F. to generate a TFA salt.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][C:14]([CH3:23])=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].[H][H]>CCOC(C)=O.O=[Pt]=O>[OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH:14]([CH3:23])[CH2:15][C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: [H][H]
Reactant: COC(=O)C=C(C)C=C(C)CC(C)CCCCC1OC(=O)C1CO
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)CC(C)CC(C)CCCCC1OC(=O)C1CO

Procedure:
49 mg (0.144 mmole) of Methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate in 5 ml of EtOAc was added 3 mg of platinium oxide. This mixture was hydrogenated at room temperature and 1 atom for N30 minutes (NO. 144 mmole (1 eq) of hydrogen was consumed). The solution was filtered and the filtrate was concentrated to dryness afforded methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([F:23])[CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:23][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(F)c1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(F)c1

Procedure:
The title compound is prepared in analogy to example 3 from N-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Light yellow solid. MS: m/e=321.2 (M++H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([O:33][C:34]1[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50]OS(C)(=O)=O)=[CH:43][C:42]=2[O:56][CH3:57])=[C:38]([CH3:58])[N:37]=[C:36]([NH2:59])[N:35]=1)(=[O:32])=[O:31]>CC#N.O>[NH2:59][C:36]1[N:35]=[C:34]([O:33][S:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:21])(=[O:32])=[O:31])[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][N:1]3[CH2:5][CH2:4][CH2:3][C@@H:2]3[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:43][C:42]=2[O:56][CH3:57])=[C:38]([CH3:58])[N:37]=1
Reactant: COc1cc(OCCCOS(C)(=O)=O)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(R)-tert-butyl pyrrolidine-2-carboxylate (485 mg) was added to the mixture of potassium carbonate (393 mg), potassium iodide (31 mg) and the crude product from step (viii) in CH3CN (20 mL). After the mixture was stirred at 70° C. for 16 h, the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (975 mg) as a white amorphous solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.67 (1H, d), 6.39 (1H, d), 6.30 (1H, dd), 4.64 (2H, br s), 4.03-3.90 (2H, m), 3.76 (3H, s), 3.73 (2H, s), 3.20-3.00 (2H, m), 2.96-2.80 (1H, m), 2.66-2.50 (1H, m), 2.57 (6H, s), 2.46-2.30 (1H, m), 2.28 (3H, s), 2.22 (3H, s), 2.21-1.74 (6H, m), 1.43 (9H, s); LC-MS: m/z 655.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[ClH:15]>O1CCOCC1>[ClH:15].[ClH:15].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])=[CH:8][CH:9]=1
Reactant: CN(C)CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCc1ccc(N)cc1
Yield: 85 %

Procedure:
Using the compound obtained in Example 97 as a starting material and after adding a solution of hydrogen chloride (4N) in 1,4-dioxane, the same procedure of Example 2 gave 2.37 g of the titled compound (yield, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]23[CH2:33][CH:28]4[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]4)[CH2:25]2)[CH2:31]3)[CH:17]=1)[C:5]([O:7]CC=C)=[O:6].N1CCOCC1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]23[CH2:31][CH:30]4[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]4)[CH2:25]2)[CH2:33]3)[CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: C=CCOC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c(C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COc1ccc(C(=O)Oc2ccc(C(=O)O)cc2C)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2.35 g (5 mmoles) of the ester prepared in step 15 (b) above are dissolved in 50 ml of THF. Under a stream of nitrogen, 78.3 mg of tetrakis(triphenylphosphine) palladium (O) are added and then 4.4 ml (50 mmoles) of morpholine are slowly introduced. The reaction mixture is then stirred at ambient temperature for 2 hours and evaporated to dryness. The residue is ground in ethyl ether and the solid is filtered. The solid is then introduced into 10 ml of water, acidified to pH 1, extracted with a 3/1 mixture of ethyl ether and THF. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue is ground in 50 ml of ethyl ether, filtered and dried. 1.6 g (70% yield) 277° C. are obtained.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[N:21]([CH3:31])[N:20]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[N:21]([CH3:31])[N:20]=[C:19]([CH2:18][O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]([OH:32])=[O:5])[CH:9]=[CH:10]4)[CH:23]=2)=[CH:25][CH:26]=1
Reactant: Cn1nc(COc2ccc3c(ccn3CC(=O)OC(C)(C)C)c2)cc1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(COc2ccc3c(ccn3CC(=O)O)c2)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for example 1 f], {5-[5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {5-[5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH:17]([CH3:18])[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[ClH:28].[CH3:29][CH:30]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:31](=[O:32])[CH:30]([CH3:29])[CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:7]2[C:8]3[CH:17]([CH3:18])[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CC(CCN1CCCCC1)C(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CCS1

Procedure:
1,2-dihydro-10-hydroxy-8-(3-methyl-2-octyl)-1,5,5-trimethyl-3H,5H-thiopyrano[2,3-c][1]benzopyran is reacted with 2-methyl-4-piperidinobutyric acid hydrochloride in methylene chloride in the presence of dicyclohexylcarbodiimide, according to the procedure of Example 28, to produce the desired ester.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:9])[C:5](C)=[CH:6][CH:7]=1.CO[C:12]1[C:13](=[NH:21])[CH:14]=[C:15](OC)[C:16](=[NH:18])[CH:17]=1>O.N>[CH:2]1[C:7](=[N:18][C:16]2[CH:17]=[CH:12][C:13]([NH2:21])=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4](=[O:9])[CH:3]=1
Reactant: COC1=CC(=N)C(OC)=CC1=N
Reactant: Cc1ccc(N)cc1O
Agent: N
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 0.33 h
Yield: 3.2 %

Procedure:
0.02 mole (0.246 g) 3-amino-6-methyl phenol is dissolved in 30 cc water to which 5 cc ammonia 22° Be were added. To this solution there is added 0.02 mole (0.332 g) 2,5-dimethoxy benzoquinone diimine from the first stage in solution in 60 cc water. The mixture is agitated for 20 minutes. Thereafter the reaction mixture is filtered off, yielding 0.125 g of said indoaniline which exhibits a melting point of 104°.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)=[C:27]([C:28]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:29])[CH:31]=1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 13. MS (ESI): mass calculated for C24H23F4N7O, 501.49; m/z found 502.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.70 (d, J=4.9, 2H), 8.38-8.31 (m, 1H), 7.24-7.17 (m, 1H), 7.14-7.02 (m, 2H), 5.86 (br s, 1H), 4.06-2.78 (m, 16H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C1OCCOCCOCCOCCOCCOC1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:11])([F:12])[F:13]
Reactant: OC(c1ccc(F)cc1Br)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
Add 1-(2-bromo-4-fluoro-phenyl)-2,2,2-trifluoro-ethanol (12 g, 43.9 mmol) in 20 mL DCM to a stirred suspension solution of 3,3,3-triacetoxy-3-iodophthalide (52 g, 122.6 mmol) and 18-crown-6 (0.6 g) in DCM (400 mL). Stir the mixture at RT for 4 h and pour into a solution of NaHCO3/NaS2O3. Wash the organic layer with water, dry over sodium sulfate, and concentrate in vacuo. Purify the resulting crude product by FCC (20% ethyl acetate in hexane as the eluant) to give the title compound as a pale yellow oil (9 g, 76%). 1H NMR (400 MHz, CDCl3) δ 7.77 (m, 1H), 7.51 (m, 1H), 7.20 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(OP(=[S:18])(O)OCC)C>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[S:18])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOP(O)(=S)OCC
Solvent: O
Product: NC(=S)c1ccc(O)cc1
Temperature: 80 °C
Yield: 86.3 %

Procedure:
In a round bottomed flask, 4-hydroxybenzonitrile (5.00 g, 41.9 mmol), diethylthiophosphoric acid (7.02 g, 41.9 mmol), and water (8 ml) were heated with stirring to about 80° C. for about thirty minutes. An additional 10 ml of water was then added to the suspension, and the reaction was heated for about another one hour. The mixture was then allowed to stir for about sixteen hours at room temperature and was then extracted with water and 1:1 ether/ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (silica gel; hexanes to ethyl acetate). The product was isolated as a yellow solid (5.54 g, 87% yield). 1H NMR (CD3OD): δ6.74 (d, 2H, J=9.1 Hz), 7.83 (d, 2H, J=8.7 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[N:15](C3CCCCO3)[CH:16]=[N:17][C:13]=2[C:12]=1[CH3:26])C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[NH:15][CH:16]=[N:17][C:13]=2[C:12]=1[CH3:26]
Reactant: Cc1c(CN(C)C(=O)OC(C)(C)C)ccc2c1ncn2C1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc2[nH]cnc2c1C
Yield: 81.5 %

Procedure:
A solution of 262 (100 mg, 0.28 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at RT for 30 min. The solvent was removed and the residue was dissolved in EtOAc and neutralized with ammonia. The organic layers were separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 40 mg (82%) of N-methyl(4-methyl-1H-benzo[d]imidazol-5-yl)methanamine (264): MS (ESI) m/z=176.3 [M+l]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][N:16]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(CN=[N+]=[N-])C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)C(CN)C1

Procedure:
To a stirred solution of 3-azidomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.624 mmol, 0.16 g) in ethyl acetate (5 mL) was added 10% palladium on carbon (0.1 g, wet). The resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 4 h. The catalyst was filtered through a pad of celite and the filtrate was concentrated to provide 3-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.