Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40]Br)[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:36]
Reactant: CCOC(=O)CCBr
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (25.1 mg, 0.06 mmol, 1.0 equiv; Example 147) in anhydrous DMF (1 mL) was added lithium aluminium hydride (2.3 mg, 0.06 mmol, 1.0 equiv; [CAS RN 16853-85-3]) and the reaction mixture stirred at rt. After 30 min, 3-bromo-propionic acid ethyl ester (13.0 mg, 10 μL, 0.072 mmol, 1.2 equiv; [CAS RN 539-74-2]) was added and the reaction mixture heated by microwave irradiation to 150° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 2.4 mg (8%) of the title compound as a light brown oil. MS (ISP): 518.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][CH:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:19])[N:10]([CH3:20])[CH2:9][C:8]=2[CH:21]=1)([OH:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([N:13]1[C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:21][C:8]=2[CH2:9][N:10]([CH3:20])[C:11](=[O:19])[CH:12]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Solvent: CC(=O)O
Product: COC(=O)CC1C(=O)N(C)Cc2cc(C(=O)O)ccc2N1C(C)=O
Reaction time: 48 h
Yield: 78 %

Procedure:
Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (2.0 g, 8.6 mmol), acetic anhydride (25 mL) and acetic acid (1 mL) were heated to reflux. After 48 h, the reaction was concentrated, and the residue was diluted with H2O (20 mL) and MeOH (15 mL). The resulting solution was concentrated to give the tide compound (1.8 g, 78%): 1H NMR (400 MHz, DMSO-d6) δ1.7-1.8 (s, 3H), 2.2-2.6 (m, 2H), 2.9-3.0 (s, 3H), 3.5-3.6 (s, 3H), 4.2-4.3 (d, 1H), 4.7-4.8 (d, 1H), 5.8-5.9 (t, 1H), 7.5-7.6 (d, 1H), 7.9-8.0 (dd, 1H), 8.1-8.2 (d, 1H); MS (ES) m/e 335.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][Li:8])=[O:6].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[Si:18]([O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][Li:8])=[O:6])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [Li]OC(=O)CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: [Li]OC(=O)CCCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a suspension of 4-hydroxybutanoyloxylithium (5.17 g, 41.03 mmol) and 1H-imidazole (4.19 g, 61.55 mmol) in DMF (20 mL) was added TBSCl (7.42 g, 49.04 mmol) in portions at r.t. The reaction mixture was then stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate three times. The organic phase separated and washed with water twice, brine and dried with anhydrous Na2SO4. It was then concentrated to give the title compound as colorless oil (8.0 g, 89%). [M+H] Calc'd for C10H21LiO3Si, 225; Found, 225.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(OC([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[C:48]3[N:49]([CH2:54][C:55]#[C:56][CH3:57])[C:50](=[O:53])[N:51]([CH3:52])[C:47]=3[C:46](Br)=[CH:45][N:44]=2)[CH2:39][CH2:38]1)=O)(C)(C)C.[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>CN1CCCC1=O.[Cu]Cl.ClCCl>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[CH2:54]([N:49]1[C:48]2[C:43]([N:40]3[CH2:39][CH2:38][NH:37][CH2:42][CH2:41]3)=[N:44][CH:45]=[C:46]([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([NH2:10])=[O:9])[C:47]=2[N:51]([CH3:52])[C:50]1=[O:53])[C:55]#[C:56][CH3:57]
Reactant: NC(=O)c1ccccc1O
Reactant: CC#CCn1c(=O)n(C)c2c(Br)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(=O)n(C)c2c(Oc3ccccc3C(N)=O)cnc(N3CCNCC3)c21
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Salicylamide (0.030 g), cesium carbonate (0.071 g), 2,2,6,6-tetramethyl-3,5-heptanedione (0.003 mL), and copper(I) chloride (0.006 g) were added to a solution of 4-[7-bromo-3-(2-butynyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-carboxylic acid t-butyl ester (0.050 g) in 1-methyl-2-pyrrolidone (1 mL). This was heated under nitrogen atmosphere at 130° C. for 14 hours. The reaction solution was cooled, dichloromethane (2 mL) and trifluoroacetic acid (3 mL) were added, and this was stirred for two hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography to give the title compound (0.007 g).
Reaction SMILES: [S:1]1[C:5]([C:6]2([OH:16])[CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1.Cl.[OH-].[Na+]>CN(C=O)C>[OH:16][C:6]1([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: OC1(c2cncs2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1CCC(O)(c2cncs2)CC1
Temperature: 60 °C

Procedure:
A 5-L 4-neck round bottom flask equipped with a thermocouple, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with ketal 9 as prepared in the previous step (316.3 g, 1.30 mol) and DMF (238.0 mL) with stirring. A solution of 2 N HCl (1.13 L, 2.26 mol) was added over 2 min; the mixture was stirred at 26° C. for 5 min, warmed up to 60° C., and stirred for 3 h. The progress of the reaction was monitored by HPLC and LC-MS. The reaction was cooled to 0° C. in an ice-water bath, and the aqueous (pH=2˜3) was adjusted to an alkaline (pH=10˜11) by dropwise addition of 4 N NaOH solution with fast agitation. The resulting alkaline slurry was stirred at 0° C. for 1 h; the solid was collected by filtration, washed with cold water (100 mL), dried under air-suction for 1 h, and then placed in a vacuum drying oven under house vacuum (120 mmHg) at 50° C. for 48 h to afford the title compound, 10 as a beige crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:33])[C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:33])[C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])=[CH:13][CH:12]=1)[CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)[C@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)[C@H]2CCCN2C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
300 mg of the compound [52-1] was dissolved in a mixed solvent of 6 mL of tetrahydrofuran and 6 mL of methanol, then 100 mg of a carbon catalyst of 20% palladium hydroxide was added thereto, and the mixture was stirred for 2.5 hours at room temperature under hydrogen atmosphere. The catalyst was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 6 mL of tetrahydrofuran, then 147 μL of 37% formaldehyde solution and 420 mg of sodium triacetoxyborohydride were added thereto, and the mixture was stirred for 1.5 hours at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, the solution was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1), and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Thereafter, the insolubles were filtered, and the filtrate was concentrated under reduced pressure, to obtain 220 mg of tert-butyl[(1S)-1-(4-{hydroxy[(2R)-1-methylpyrrolidin-2-yl]methyl}phenyl)ethyl]carbamate [54-1] (hereinafter, referred to as the compound [54-1]).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].B(O)(O)[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])=[CH:12][CH:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccsc1Br
Product: Cc1ccc(-c2sccc2C(=O)O)cc1

Procedure:
prepared by reaction of 2-bromo-thiophene-3-carboxylic acid with p-tolylboronic acid. LC-MS (basic): tR=0.53 min; [M−H]−=217.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=O.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH3:14])=[O:13]
Reactant: CCCC(N)CCC
Reactant: COc1ccccc1C=CC(=O)O
Product: CCCC(CCC)NC(=O)C=Cc1ccccc1OC

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-methoxy-phenyl)-acrylic acid and 4-heptylamine. MS (M+H, 276.2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1.C(OCC)(=O)C>CS(C)=O>[CH:26]([O:25][C:18]1[CH:17]=[C:16]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])([CH3:28])[CH3:27]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 63.7 %

Procedure:
1.7 g of potassium carbonate and 1.0 g of 4-amino-1-methylpiperidine are successively added to a solution of 1.6 g of 4-fluoro-2-isopropoxy-1-nitrobenzene in 13.5 ml of dimethyl sulfoxide. The reaction mixture is heated at 120° C. for 3 h and is then cooled to ambient temperature and poured into a mixture of 150 ml of ice-cold water and 100 ml of ethyl acetate. After settling out, the organic phase is separated and the aqueous phase is extracted twice with 70 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 90 g silica cartridge, elution being carried out with a 97.5/2/0.5 v/v/v dichloromethane/methanol/20% aqueous ammonia mixture at a flow rate of 50 ml/min, so as to obtain 1.5 g of (3-isopropoxy-4-nitrophenyl)(1-methylpiperidin-4-yl)amine in the form of a bright yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[S:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cc(F)ccc1S
Solvent: CC#N
Product: COc1cc2nccc(Sc3ccc(F)cc3C(=O)O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
5-Fluoro-2-mercaptobenzoic acid (278 mg) and 4-chloro-6,7-dimethoxyquinoline (300 mg) were suspended in acetonitrile (6 ml), and the suspension was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, the mixture was neutralized with sodium hydrogencarbonate and was then extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give 2-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoic acid (152 mg, yield 31%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1F>C(#N)C>[Br:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Br)c1
Yield: 98.7 %

Procedure:
Morpholine (7.92 mL, 90.9 mmol) was added to a solution of 2-bromo-1-fluoro-4-nitrobenzene (10 g, 45.5 mmol) in acetonitrile (100 mL) and the mixture was heated under reflux for 6 h. Volatile material was removed by evaporation and the residue was diluted with water (100 mL) then extracted with ethyl acetate (2×100 mL). The organic extracts were combined, dried and concentrated to give the title compound (12.9 g, 99%) as a solid; 1H NMR δ 8.40 (1H, s), 8.20 (1H, d), 7.10 (1H, d), 3.80-3.70 (4H, m), 3.20-3.10 (4H, m); MS m/e MH+ 287.
Reaction SMILES: [F:1][C:2]([F:29])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[C@@H:13](O)[C@H:12]([N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]3=[O:27])[C:11]=2[CH:28]=1)[C:3]([F:6])([F:5])[F:4].CS(Cl)(=O)=O.C(N(CC)CC)C>O1CCCC1>[F:29][C:2]([F:1])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]3=[O:27])[C:11]=2[CH:28]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=c1ccccn1[C@@H]1c2cc(C(F)(F)C(F)(F)F)ccc2OC(CF)(CF)[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1ccccn1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of 0.15 g of trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ol, 0.07 g of methanesulfonyl chloride, 0.08 g of triethylamine and 10 ml of tetrahydrofuran was stirred at room temperature for 8 hours and the solvent was distilled off. Water was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was dissolved in 4 ml of tetrahydrofuran and 0.06 g of sodium hydrate (60%) was added thereto with stirring under ice-cooling. The mixture was then stirred at room temperature for 66 hours. Ice water was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.09 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 137°-138° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[CH:6][C:5]=1[OH:19])([CH3:3])[CH3:2].[CH3:20][O-:21].[Mg+2].C[O-].C=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[C:6]([CH:20]=[O:21])[C:5]=1[OH:19])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CCCCCCCCCc1ccc(O)c(C(C)C)c1
Agent: C=O
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1cc(C=O)c(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 20 %

Procedure:
2-Isopropyl-4-nonylphenol (3a) (239.4 g, 0.914 mol) in toluene (470 mL) was placed in a 4-neck RBF equipped with a thermometer, a condenser, and a mechanical stirrer. To the solution was added methanolic magnesium methoxide (685 mL of 7.4 wt. %, d. 0.816 g/mL). The methanol was distilled off gradually so that the pot temperature was raised to 100° C. Then solid paraformaldehyde (80 g, 2.7 mol) was introduced in portions for 30 mins. maintaining the same temperature. Crude product was distilled and further purified by flash column chromatography to obtain 3-isopropyl-5-nonylsalicylaldehyde (52.6 g) in 20% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(O)C.CCOCC>[Pd].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:28])=[O:29])[CH:25]=[CH:26][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
A suspension of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (11.2 g, 22.4 mmol) and palladium on carbon (1.45 g, 10%, wet, Degussa, E101 NE/W) in a 2:1 mixture of THF and ethanol (150 ml) was stirred under a hydrogen atmosphere (2-3 balloons) at 50° C. for 18 h. The reaction mixture was cooled to 25° C. then was filtered through Celite. The filtrate was concentrated under reduced pressure and the red-orange residue was purified by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) to give a dark red oil. This material was dissolved in CH2Cl2 (40 ml) and Et2O (200 ml) was added. Concentration of this mixture to approximately 60 ml volume under reduced pressure afforded a pink solid. This material was collected by vacuum filtration, was washed with Et2O (2×30 ml), and was air-dried to afford 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (7.23 g, 69%). LCMS (Method G, ESI): RT=0.87 min, m+H=472.3; 1H NMR (400 MHz, DMSO) δ 8.04-7.99 (m, 2H), 7.70-7.65 (m, 1H), 7.61-7.55 (m, 3H), 7.49 (d, J=4.2 Hz, 1H), 6.78 (d, J=4.3 Hz, 1H), 5.11 (d, J=8.7 Hz, 1H), 4.37 (s, 1H), 3.94-3.86 (m, 2H), 2.95 (s, 1H), 2.54-2.48 (m, 2H), 1.92-1.79 (m, 3H), 1.40 (s, 9H), 1.38-1.27 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]([Cl:22])([Cl:21])[CH:7]([OH:20])[CH:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>CN(C)C=O>[Cl:22][C:6]([Cl:5])([Cl:21])[CH:7]([O:20][C:1](=[O:3])[CH3:2])[CH:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Solvent: CN(C)C=O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Yield: 40.1 %

Procedure:
8.0 g (0.1 mol) of acetyl chloride were added to 31.5 g (0.1 mol) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one in 100 ml of dimethylformamide at room temperature. Thereafter, the mixture was heated under reflux for 4 hours. It was left to cool and concentrated by distilling off the solvent in vacuo. The residue was taken up in methylene chloride and the methylene chloride solution was washed with aqueous sodium bicarbonate solution and dried over sodium sulphate. The solvent was distilled off and the residue was taken up in 100 ml of diisopropyl ether. After the diisopropyl ether mixture had stood for several hours, colorless crystals precipitated. 14.3 g (40% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethylhexan-4-one were obtained as the pure diastereomer of the A* form of melting point 128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c2cnccc12
Solvent: O=CO
Solvent: ClCCl
Product: O=C(O)Cc1ccc(F)c2cnccc12
Reaction time: 16 h

Procedure:
To a solution of the above ester (200 mg) in DCM (2 mL) was added formic acid (3 mL). The reaction was sealed with a Teflon cap and heater to 50° C. for 16 h. The solvent was removed and the crude product was used without further purification. LCMS showed an m/z of 206.1 with a retention time of 0.437 min, method [1].
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH3:24][CH:25]([CH3:30])[CH:26]([OH:29])[C:27]#[CH:28]>>[OH:29][CH:26]([C:27]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:28]=1)[CH:25]([CH3:30])[CH3:24]
Reactant: C#CC(O)C(C)C
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CC(C)C(O)c1cn(C2CCc3c(CC(=O)O)c4ccccc4n3C2)nn1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 4-methylpent-1-yn-3-ol. MS (+ESI) m/z: 369.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:13][O:14]C(Cl)Cl.CCOCC>C(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[CH:13]=[O:14])[CH3:12]
Reactant: COC(Cl)Cl
Reactant: CCOc1ccc(OCC)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1ccc(OCC)c(C=O)c1
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A mixture of 1,4-diethoxybenzene (24.9 g 0.150 mole) and 1,1-dichloromethyl methyl ether (18 g., 0.157 mole) in methylene chloride (80 ml.) was added with stirring during 20 minutes to a solution of stannic chloride (39 g., 0.150 mole) in methylene chloride (150 ml.) at approximately 0° C. The solution was then stirred at this temperature for 5 minutes and quenched by addition of aqueous hydrochloric acid (6 N., 100 ml.) which was added rapidly. The organic phase was separated washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate by evaporation under reduced pressure to yield a crystalline solid (29 g.) m.p. 57°-59° C. Recrystallation (from ether) gave 2,5-Diethoxybenzaldehyde (27.1 g., 0.138 mole, 93%) m.p. 60°-61° I.R.: 1738 cm-1 (aldehyde CO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][O:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15][CH2:14]2)[CH3:11])=[O:23])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-propyl ester as colorless solid, MS: 418 (MH+, 1Cl).