Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=CC2N=C(NCC3CCNC3)OC=2C=1.Cl.C(OC([N:26]1[CH2:30][CH2:29][C@@H:28]([CH2:31][NH2:32])[CH2:27]1)=O)(C)(C)C.Cl[C:34]1[S:35][C:36]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:37]=2[N:38]=1>O1CCOCC1>[ClH:1].[F:43][C:41]1[CH:40]=[CH:39][C:37]2[N:38]=[C:34]([NH:32][CH2:31][C@@H:28]3[CH2:29][CH2:30][NH:26][CH2:27]3)[S:35][C:36]=2[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc2nc(NC[C@@H]3CCNC3)sc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride (example 1, step 2) the title compound was prepared from (S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloro-6-fluoro-benzothiazole (commercially available) and subsequent cleavage of the tert-butyloxy carbonyl-protecting group through treatment with HCl in dioxane. MS (m/e): 252.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28].CCCCCC>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:11]([C:12]([NH:28][CH2:27][C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Reactant: NCc1cccs1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
A solution of 2.1 g (10.0 mmol) 2-chloroquinoline-3-carboxylic acid in thionyl chloride (60 ml) was heated for 2 h at 85° C. Then excess thionyl chloride was removed under vacuum. The residue was taken up with DCM (60 ml) and the solution was cooled to 0° C. and then mixed with 4.0 ml (30.0 mmol) NEt3 and 1.03 ml (10.0 mmol) thiophene-2-methylamine. After stirring for 90 min at RT it was diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 1.44 g (4.8 mmol, 48%) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([Si](C)(C)C)=[C:7]2[CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].[OH-].[Na+]>C(#N)C>[NH4+:9].[OH-:3].[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:17][CH2:18][CH2:19][OH:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(=O)c1ccc2[nH]cc(CCCO)c2c1
Product: [NH4+]
Temperature: 23 °C
Reaction time: 24 h
Yield: 167.5 %

Procedure:
To a solution of 5-acetyl-3-[3-(t-butyldimethylsiloxy)propyl]-2-trimethylsily 1-1H-indole (1.8 g, 5 mmol) in acetonitrile (100 mL) was added a 50% HF solution (4 mL) After stirring for 24 h at 23° C., the reaction was made basic (pH 10) by the addition of 50% NaOH solution and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated NaCl and next with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (CH2Cl2 :MeOH:NH4OH; 95:5:0.5) of the concentrate afforded 1-[5-acetyl1H-indol-3-yl]-3-propanol (0.91 g, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:24][CH2:25][CH:26]=[CH2:27])[CH2:18][C:19](OCC)=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:24][CH2:25][CH:26]=[CH2:27])[CH2:18][CH2:19][OH:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNC(CC(=O)OCC)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(CCO)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of (R)-3-(1-allylamino-2-ethoxycarbonylethyl)piperidine-1-carboxylic acid benzyl ester (0.427 g, 1.14 mmol) in THF (20 mL) was added a solution of lithium borohydride in THF (2M, 5.7 mL, 11.4 mmol). The mixture was stirred at RT for 10 min then at 40° C. for 22 h. After cooling to RT, water was added with initial caution. The mixture was extracted twice with EtOAc, and the combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound (0.264 g, 70%) as a colourless gum. LCMS (Method B): RT 2.00 min [M+H]+ 333.
Reaction SMILES: [OH-].[K+].[C:3]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=[N:34][O:35][CH:36]=[CH2:37])[C:29]([O:31]CC)=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[K]>C(O)C.O1CCOCC1>[C:3]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=[N:34][O:35][CH:36]=[CH2:37])[C:29]([OH:31])=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: C=CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C

Procedure:
20 ml of a solution of 0.5 M of potassium hydroxide in absolute ethanol and 12 ml of absolute ethanol were added at room temperature to a mixture of 3.227 g of the product of Step D in 3.2 ml of dioxane and the mixture was stirred at 50° C. under argon for 1 hour during which a potassium salt crystallized. The mixture cooled to 20° C. and was vacuum filtered and the recovered product was rinsed with ethanol and was taken up in a mixture of 50 ml of ethyl acetate and 50 ml of distilled water. The mixture was acidified with 6 ml of 2 N hydrochloric acid and was stirred until 2 homogeous phases were obtained. The organic phase was decanted and was washed 3 times with 20 ml of distilled water. The wash waters were extracted with ethyl acetate and the combined organic phases were dried and vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was concentrated to a volume of 15 ml and was iced at 0° to 5° C. The mixture was vacuum filtered and the recovered product was rinsed with ethyl acetate and dried to obtain 2.53 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-vinyloxyiminoacetic acid which was used as is for the next step. A sample after crystallization melted at 150° C.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O.ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:20](=[O:21])[N:19]([CH3:18])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:8][CH:7]=1)=[O:11]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccn1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccn2)cn1)c1ccccc1
Yield: 54.8 %

Procedure:
A solution of pyridine-2-carboxylic acid (6-hydroxy-pyridin-3-yl)-amide hydrochloride (0.50 g, 1.99 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.54 g, 4.81 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 1 hour. Water was added and the solids were isolated by suction, redissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (0.38 g, 55% yield) as a white solid.
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].P(Cl)(Cl)([Cl:14])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([Cl:14])[N:1]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]cnc2n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of guanine (4.5 g, 30 mmol), tetraethylammonium chloride (30 mmol), phosphorus oxychloride (16.5 ml and acetonitrile (60 ml) was placed in a flask in an ultrasonic bath at 60° C. for 2 hours. The mixture was then heated under reflux for 90 minutes and allowed to cool. The solid material was filtered off and suspended in water. The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide and back to pH 7 with dilute hydrochloric acid. Continuous extraction with ethyl acetate afforded 2-amino-6-chloropurine as a white solid (1.55 g, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[S:19]([OH:22])(=[O:21])=[O:20].CCOCC>C(OC)(=O)C1C(=CC=CC=1)C(OC)=O>[CH3:17][O:16][C:14]1[CH:15]=[C:2]([OH:1])[C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:12][C:13]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: O=S(=O)(O)Cl
Solvent: CCOCC
Solvent: COC(=O)c1ccccc1C(=O)OC
Product: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
11.4 g of 2-hydroxy-4-methoxybenzophenone were dissolved in 30 ml of dimethyl phthalate at 80° C., and 3.5 ml of chlorosulfonic acid were added dropwise at this temperature. Stirring was carried out for a further 4 hours at 80° C., the mixture was cooled to room temperature and 25 ml of ether were added to the solution. The precipitate was filtered off under suction, washed with ether and hexane and dried under reduced pressure at 30° C. 10 g of 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid of melting point 112°-114° C. were obtained (water content 7.7%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[O:18]([CH2:25]C(Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:29]1([CH2:39][NH2:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[Cl:14][CH:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:25][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:9]([C:15]([NH:40][CH2:39][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[O:17])[CH2:10]1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: O=C(NCc1cccc2ccccc12)[C@@H]1CC(=CCl)CN1C(=O)COc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=435.6.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(C=O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a stirring solution of (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (10 g, 37 mmol) and 4-hydroxybenzaldehyde (4.5 g, 37 mmol) in THF (100 mL) was added triphenylphosphine (12.2 g, 46.5 mmol) and Diisopropyl azodicarboxylate (11.2 g, 55 mmol) at 0° C., then stirred at RT for 12 h. RM diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to pale brown oil. Crude was purified by column (100-200 silica) using 8% ethyl acetate to get the titled compound as white solid (5 g, Yield: 36.2%). 1H NMR (300 MHz, CDCl3): δ 9.81 (s, 1H), 7.74-7.77 (d, 2H), 7.58-7.61 (m, 2H), 7.24-7.29 (m, 5H), 6.97-6.99 (d, 2H), 6.85-6.87 (d, 2H), 5.13 (s, 2H), 4.98 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:17]([C:18](=O)[CH:19]=1)=[CH:16][CH:15]=[C:14]1[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]1)=[O:5])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[O:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(=O)c2ccc3ncccc3c2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc3c(c2O1)CCCN3
Yield: 41.4 %

Procedure:
8-Oxo-8H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester (2.0 g, 7.4 mmole) was dissolved in 200 mL of ethanol and 0.50 g of 20% palladium hydroxide on carbon added. The mixture was treated with 60 psi of hydrogen on a Parr apparatus for 48 hours, then filtered through celite and concentrated in vacuum. Thin layer chromatography on silica gel vs. a starting material standard indicated that the reaction was incomplete. The material was redissolved in 150 mL of acetic acid, 0.50 g of 20% palladium hydroxide on carbon added, and the mixture again treated with 60 psi of hydrogen for 48 hours. It was then filtered through celite, concentrated in vacuum and column chromatographed on silica gel with 2% ethanol in chloroform as eluant to give 0.80 g of 1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester. 1H-NMR (CDCl3): doublet 6.65 δ (1H); doublet 6.1 δ (1H); multiplet 4.7 δ (1H); quartet 4.25 δ (2H); broad singlet 3.65 δ (1H); multiplet 3.2 δ (2H); multiplet 2.65 δ (4H); multiplet 2.2 δ (2H); multiplet 1.95 δ (2H); triplet 1.25 δ (3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH2:22][O:23][C:24]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])([CH2:7][O:8][C:9]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45]>O1CCCC1.O>[CH:59]1[C:60]2[CH:48]([CH2:47][O:46][C:44]([NH:1][CH2:2][C:3]([CH2:7][O:8][C:9]([C:10]([F:13])([F:12])[F:11])([C:14]([F:17])([F:16])[F:15])[C:18]([F:19])([F:21])[F:20])([CH2:22][O:23][C:24]([C:29]([F:30])([F:31])[F:32])([C:25]([F:26])([F:27])[F:28])[C:33]([F:34])([F:35])[F:36])[C:4]([OH:6])=[O:5])=[O:45])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:55]=2[CH:56]=[CH:57][CH:58]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a stirred solution of amino acid 1 (10.1 g, 17.2 mmol) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium carbonate (4.6 g, 42.9 mmol). After all the sodium carbonate was dissolved, the resulting mixture was cooled to 0° C. and 9-fluorenylmethyl chloroformate (6.7 g, 25.9 mol) was added in three portions. The resulted reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuo and the residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=5/1) to give the acid 2 as a white solid (13.3 g, 96%). mp. 104-105° C.; 1H NMR (400 MHz, CD3OD) δ 3.45 (s, 2H), 4.16 (m), 4.27 (m, 4H), 4.46 (d, J=8.8 Hz, 2H) 7.26 (t, J=7.2 Hz, 2H), 7.35 (t, J=7.2 Hz, 2H), 7.60 (d, J=7.6 Hz, 2H), 7.74 (d, J=7.2 Hz, 2H); 19F NMR (376 MHz, CD3OD) δ −71.00 (s); 13C NMR (100.7 MHz, CD3OD) δ 36.9, 42.8, 53.7, 68.2, 69.0, 80.9 (m), 120.9, 121.7 (q, J=292.6 Hz), 126.2, 128.1, 128.8, 142.6, 145.2, 158.8, 174.4; MS (CI) m/z 808 (M++1, 100); HRMS (CI) Calcd for C28H20F18NO6: 808.1003, Found: 808.1010.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1)=O>C1COCC1>[C:7](/[CH:9]=[CH:18]/[C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1)#[N:8]
Reactant: N#CC1(C=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#C/C=C/C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in TBF (1.12 mL) at 0° C. was added slowly dropwise a solution of diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and the reaction was warmed to ambient temperature. The solution was then re-cooled to 0° C. and a solution of 1-formylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bath was removed and the reaction was stirred for 3 hours at ambient temperature. The mixture was then diluted with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Al](Cl)(C)C.[CH3:12][C:13]1[O:14][C:15]2[CH:21]=[C:20]([C:22](OCC)=[O:23])[CH:19]=[C:18]([O:27][CH:28]3[CH2:31][N:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29]3)[C:16]=2[CH:17]=1>ClCCl>[CH3:12][C:13]1[O:14][C:15]2[CH:21]=[C:20]([C:22]([NH:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[N:6]=3)=[O:23])[CH:19]=[C:18]([O:27][CH:28]3[CH2:31][N:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29]3)[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1cc(OC2CN(S(C)(=O)=O)C2)c2cc(C)oc2c1
Reactant: Cn1ncc(N)n1
Agent: C[Al](C)Cl
Solvent: ClCCl
Product: Cc1cc2c(OC3CN(S(C)(=O)=O)C3)cc(C(=O)Nc3cnn(C)n3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of 2-methyl-2H-1,2,3-triazol-4-amine (267 mg, 1.98 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH3)2Cl (1.98 mL, 1.98 mmol, 1M in hexanes) drop-wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-methyl-4-{[1-(methylsulfonyl)azetidin-3-yl]oxy}-1-benzofuran-6-carboxylate (70 mg, 0.198 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CH2Cl2, washed with brine and dried over Na2SO4. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (95/5 to 85/15) to give the title compound (55 mg, 68%) as a white solid after evaporation of the solvents. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3 H) 2.94 (s, 3 H) 4.06-4.15 (m, 3 H) 4.16 (d, J=4.80 Hz, 2 H) 4.39 (dd, J=9.60, 6.32 Hz, 2 H) 5.05-5.23 (m, 1 H) 6.54 (s, 1 H) 6.97 (s, 1 H) 7.54 (s, 1 H) 8.12 (s, 1 H) 8.46 (s, 1 H); MS (ESI, pos): 406.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=[O:34].[CH2:37]([O:39][C:40](=[O:49])[C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[C:43]([F:48])[CH:42]=1)[CH3:38]>C(Cl)Cl>[CH2:37]([O:39][C:40](=[O:49])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:18](=[O:19])[C:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[OH:34])=[C:43]([F:48])[CH:42]=1)[CH3:38]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)C(O)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (60 mg, 161 μmol) in CH2Cl2 (0.8 ml) under an argon atmosphere was added pyridine (16 μl, 202 μmol) and thionyl chloride (14 μl, 193 μmol). 4-Amino-3-fluoro-benzoic acid ethyl ester (29 mg, 161 μmol; CAS Reg. No. 73792-12-8) and pyridine (16 μl, 202 μmol) were added and the reaction mixture was stirred at ambient temperature for 48 h. Ice water/25% aqueous HCl solution 1/1 was added and the mixture was extracted three times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a brown solid which was purified by preparative thick layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (9 mg, 16 μmol; 10%) as colorless solid. MS: m/e=554.4 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[S:15][C:16]2[CH2:24][CH2:23][C:22]3[NH:21][N:20]=[CH:19][C:18]=3[C:17]=2[N:25]=1>C1COCC1>[CH3:3][CH:2]([CH3:4])[C:1]([N:21]1[C:22]2[CH2:23][CH2:24][C:16]3[S:15][C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)=[N:25][C:17]=3[C:18]=2[CH:19]=[N:20]1)=[O:5]
Reactant: CC(C)C(=O)Cl
Reactant: c1ccc(Nc2nc3c(s2)CCc2[nH]ncc2-3)nc1
Solvent: C1CCOC1
Product: CC(C)C(=O)n1ncc2c1CCc1sc(Nc3ccccn3)nc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
According to Scheme 5: Isobutyryl chloride (0.37 mmol, 39 μL) was added dropwise to a solution of N-(pyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (0.37 mmol, 100 mg) in THF (2 mL) and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was quenched with a saturated solution of NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM as eluent to yield after evaporation 2-methyl-1-(2-(pyridin-2-ylamino)-4H-thiazolo[4,5-e]indazol-6(5H)-yl)propan-1-one
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19].Cl[C:23]1C=C(OCCN2CCCCC2)C=CC=1C(=O)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:23][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19]
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CCCC(=O)c1ccc(OCCN2CCCCC2)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCCN2CCCCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step B except that the 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone of Example 1 Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(2-piperidinoethoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.3 m.).