Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[Cl:6][C:7]1C=[CH:11][CH:10]=[CH:9][C:8]=1C=C.S([O-])([O-])=[O:16].[Na+].[Na+]>O>[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[CH:1]([OH:5])[CH2:3][OH:16]
Reactant: C=Cc1ccccc1Cl
Reactant: O=S([O-])[O-]
Reactant: CC(C)(C)O
Agent: [Na+]
Solvent: O
Product: OCC(O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a vigrouosly stirred mixture of AD-mix (1.4 g) in water (5 ml) and t-butanol (5 ml) at 0° C. was added 1-Chloro-2-vinyl-benzene (0.140 grams, 1.0 mmole) and stirred at 0° C. for 2 hours. To the mixture sodium sulfite (1.5 g) was added and allowed to warm to room temperature for 1 hour. The mixture was extracted with methylene chloride. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give a colorless oil (0.190 g). MW 172.61; MS (m/e) 190 (M++18).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.[Br:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>CN(C=O)C.N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:27][C:24]4[CH:25]=[N:26][C:21]([Br:20])=[CH:22][CH:23]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc(Br)nc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Yield: 47.7 %

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (9.50 g, 46.00 mmol), thionyl chloride (10.00 mL, 138.00 mmol) and DMF (4 drops) were added and the mistrure was stirred and heated at 60° C. for thirty minutes. The excess thionyl chloride was evaporated under reduced pressure. A portion of the acid chloride (23.20 mmol) was dissolved in pyridine (15 mL) and was slowly added to 6-bromopyridin-3-amine (23.20 mmol) in pyridine (10 mL). The reaction mixture was stirred at 110° C. for one hour and thirty minutes. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in dichloromethane (200 mL) and washed with 1 N NaOH (4×50 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide (4 g, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.8 g, 18 mmol) was dissolved in 150 mL dry diethyl ether under Ar, and the resulting solution was cooled in an ice water bath, while dry pyridine (8.6 mL, 106 mmol) was added, followed by the dropwise addition of oxalyl chloride (4.6 mL, 53 mmol). A precipitate formed immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. 100 mL of diethyl ether were then added, and the solids wwere removed by filitration washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 50 mL dry DCM under Ar, cooled to 0° C., added 6 mL pyridine followed by 4-bromo-2-fluoroaniline (3.4 g, 17.7 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (3.2 g, 47%) APCI (AP−): 385.1, 387.1 (M−H)−.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)[N:28](S(C)(=O)=O)[C:22]=3[CH:21]=2)=[CH:15][CH:14]=1>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:37]=[N:36][NH:35][CH:34]=4)[NH:28][C:22]=3[CH:21]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)n1c(-c2cn[nH]c2)cc2cnc(Nc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1ccc(Nc2cc3[nH]c(-c4cn[nH]c4)cc3cn2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
DBU (2 μL, 0.016 mmol) was added to a solution of N-(4-fluorophenyl)-1-(methylsulfonyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine (Example 187, 3 mg, 8.08 μmol) in DMF (54 μL). The reaction mixture was stirred for 1 hour at 50° C. and for 1 hour at 100° C. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified using preparative TLC eluting with DCM/MeOH, 90/10 to afford the title compound as a brown solid (2 mg, 84%). 1H NMR (500 MHz, CD3OD): δ 6.60 (d, J=0.9 Hz), 6.85 (s, 1H), 6.99-7.06 (m, 2H), 7.26-7.32 (m, 2H), 8.00 (br s, 2H), 8.34 (s, 1H). ESI-HRMS Found 294.1158, calculated for C16H13FN5 [M+H]+: 294.1150. MPS1 IC50 (uM): 0.140
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC(N(C)C)=O.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18](Cl)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].[OH-].[Na+]>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: Sc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1C(F)(F)F
Yield: 85.5 %

Procedure:
A mixture of 25 g of 2-mercaptopyridine, 70 ml of dimethylacetamide and 45.7 g of 3-trifluoromethyl-4-nitrochlorobenzene was heated at 80° to 90° C. and 35 g of 40% NaOH aq. solution was added to the mixture. After the reaction, the reaction mixture was poured into water and the product was extracted with ethyl ether and the ether phase was washed with a dilute NaOH aq. solution and then, with water and dried with anhydrous sodium sulfate and ether was distilled off to obtain 52 g of 2-trifluoromethyl-4-(pyridine-2-ylthio) nitrobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:20][OH:21])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:21][CH2:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazol-3-yl]methanol (112 mg) obtained from Referential Example 75 was dissolved in methylene chloride (4 mL). To the solution, triethylamine (61 μL) and methanesulfonyl chloride (34 μL) were added at room temperature, followed by stirring for 15 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as an oily product (13.8 mg, 96%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:17][C:18]1[C:19](Cl)=[C:20]([C:26](=[O:33])[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:21]([CH3:25])=[N:22][C:23]=1[CH3:24]>CC#N.CCOCC>[Br:17][C:18]1[C:19]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:20]([C:26](=[O:33])[C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[C:21]([CH3:25])=[N:22][C:23]=1[CH3:24]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CC1CCNCC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
To a solution of 4-methylpiperidine (593 mg, 5.98 mmol) and DIEA (2.1 mL, 12 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.0 g, 5.98 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 1.99 g (84%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.41-3.39 (m, 2H), 2.83 (br. s, 2H), 2.60 (s, 3H), 2.29 (s, 3H), 1.58 (d, J=12.5 Hz, 2H), 1.44 (br. s, 1H), 1.29 (d, J=6.2 Hz, 6H), 1.09-1.07 (m, 2H), 0.92 (d, J=6.2 Hz, 3H). UPLC (M+H)=399.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2(CC[CH2:11][CH2:10]2)[C:2]1=O.[ClH:15].[C:16]([OH:19])(=O)[CH3:17]>>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH2:2][C:3]12[CH2:10][CH2:11][CH2:17][C:16]1=[O:19]
Reactant: Cl
Reactant: CC(=O)O
Reactant: O=C1Nc2ccccc2C12CCCC2
Product: O=C1CCCC12CNc1ccc(Cl)cc12
Temperature: 0 °C

Procedure:
Spiro(cyclopentane-1,3'-indoline)-2'-one (18,7 g; 0.10 moles) is dissolved in acetic acid (50 ml) containing 100 mg of ferricloride hexahydrate, cooled in ice-water and drop-wise treated under agitation with a solution of clorine in acetic acid (82 ml of a solution containing 7,8 g per 100 ml). After the addition air is blown through the solution to eliminate a possible excess of clorine as well as hydrogen cloride. The crystallized product (8.7 g) is sucked off and the filtrate is concentrated in vacuum, upon which an additional product quantity (7.3 g) is obtained. After recrystallization from ethanol the substance melts at 201° - 202°C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C=O)C.[H-].[Na+].[CH:18]([Si:21]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])Cl)([CH3:20])[CH3:19]>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:21]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Iodo-1H-indole (5.0 g, 20.57 mmol) was dissolved in CH2Cl2 (50 ml) and DMF (1 ml) and cooled to 0° C. Sodium hydride (1.234 g, 30.86 mmol) was added in small portions, and the reaction mixture was stirred for 30 minutes at 0° C. Triisopropylchlorosilane (4.54 ml, 20.57 mmol) was added slowly to the reaction mixture, and stirring was continued for 1 hour. Cold water (200 ml) was added to the reaction mixture, which was extracted twice with ethyl acetate (100 ml).
Reaction SMILES: [CH3:1][O:2][CH2:3]CO.[C:6]([O:13]C(Cl)(Cl)Cl)([O:8][C:9](Cl)(Cl)Cl)=O.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][CH:27]=[C:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:20]=1>C(Cl)Cl>[CH3:18][C:19]1[N:20]=[C:21]([C:25]#[C:26][CH:27]=[C:28]2[CH2:29][CH2:30][N:31]([C:6]([O:8][CH2:9][CH2:3][O:2][CH3:1])=[O:13])[CH2:32][CH2:33]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: COCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCCOC(=O)N1CCC(=CC#Cc2cccc(C)n2)CC1
Reaction time: 0.67 h
Yield: 145 %

Procedure:
To a solution of 2-methoxyethanol (26.9 μl, 0.34 mmol) and ditrichloromethyl carbonate (37.2 mg, 0.125 mmol) in CH2Cl2 (1.5 mL) stirred at r.t., was added dropwise a solution of DEA (139 μL, 0.814 mmol) in 1.5 mL of CH2Cl2 over 30′. After 40 min., was added a solution of the Compound of Example 3 (72 mg, 0.339 mmol) and 70 μL of DEA in 0.8 mL of CH2Cl2. After 24 h, the reaction mixture was evaporated to dryness in vacuo and the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc gradient from 7:3 to 3:7 to afford the title compound (57 mg).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C([C:14]2[CH:67]=[CH:66][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23](C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[O:92]1[CH2:97][CH2:96][N:95]([CH2:98][CH2:99][OH:100])[CH2:94][CH2:93]1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([O:100][CH2:99][CH2:98][N:95]2[CH2:96][CH2:97][O:92][CH2:93][CH2:94]2)=[CH:67][CH:66]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCCN1CCOCC1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(OCCN3CCOCC3)cc2)cc1

Procedure:
Compound 88A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34B and compound 31F with 2-morpholinoethanol and 4-(benzyloxy)phenol, respectively: ESI (+)LC/MS: 314 (M+H)+.
Reaction SMILES: [C:1]1(NC(N)=O)C=CC=CC=1.[C:11]1([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])C=CC=CC=1>>[C:21]1([NH:20][C:18]([N:17]([CH3:11])[CH3:1])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Product: CN(C)C(=O)Nc1ccccc1

Procedure:
Phenylurea or 1,3-diphenylurea; 83(22):180415j.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([CH3:29])[N:28]=3)[N:3]=[CH:4][C:5]=2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[N:10]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Reactant: OB(O)c1cccnc1
Product: Cc1csc(Nc2ncc(-c3cccnc3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=334.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-pyridineboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25].O>CN(C=O)C>[CH3:3][N:4]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc([N+](=O)[O-])cc2C)cc1
Yield: 34.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.08 g (2.00 mmol)) in 2.0 ml of DMF, N-methyl-p-toluenesulfonamide (0.37 g (2.00 mmol)) was added at room temperature with stirring. To the resulting mixture, after 15 minutes' stirring at room temperature, 2-fluoro-5-nitrotoluene (0.31 g (2.00 mmol)) was added. The reaction mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated was filtered and washed to give 0.22 g (36%) of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:14]3[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=3)[OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: OC(c1ccc2c(c1)OCCO2)c1ccc2c(c1)OCCO2
Yield: 86.4 %

Procedure:
2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.87 g, 5.28 mmol), 6-bromo-2,3-dihydrobenzo[1,4]dioxine (1.25 g, 5.81 mmol), and n-butyl lithium (2.33 ml, 5.81 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol as an oil (1.37 g, 86%): 1HNMR (CDCl3) 6.87-6.82 (m, 6H, Ar), 5.63 (d, J=3 Hz, 1H, CHOH), 4.22 (s, 8H, 2CH2CH2), 2.19 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:14][C:15]1[CH:16]=[C:17]([NH3+:21])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=1)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: [NH3+]c1cccc(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Fluoro-5-nitro benzoic acid (1.48 g, 8 mmol) and 3-Fluoro-phenyl-ammonium (920 μl, 8.5 mmol) in methylene chloride/DMF (10:1) 20 ml was added 10 g PS-resin (1.54 mmol/g). The reaction mixture was stirred at room temperature for overnight and then PS-resin was moved by filtration. The filtrate was evaporated to yield the title compound as a yellow solid. (1.11 g, 50%). MS (ESI) m/z=279 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 10.89(s, 1H), 8.58-8.47(m, 1H), 7.72-7.67 (m, 1H), 7.45-7.42 (m, 1H), 7.00-6.98 (m, 1H), 6.37-6.28 (m, 2H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[N:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[C:13]=[O:14]>O1CCOCC1>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:12][C:13]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[N:2]([CH3:1])[C:3]1=[O:11])=[O:14]
Reactant: Cn1c(=O)[nH]c2ncccc21
Reactant: Cc1ccccc1CN=C=O
Solvent: C1COCCO1
Product: Cc1ccccc1CNC(=O)n1c(=O)n(C)c2cccnc21

Procedure:
Analogously to Example 1, 75 mg (0.5 mmol) of 1-methyl-1,3-dihydroimidazo[4,5-b]pyridin-2-one were reacted with 74 mg (0.5 mmol) of 1-isocyanatomethyl-2-methylbenzene in dioxane at 80° C. Yield: 11 mg (7%), M+H+: 297.05.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:17])[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@H:19]([C@H:21]1[CH2:25][N:24]([C@@H](C2C=CC=CC=2)C)[C:23](=[O:34])[CH2:22]1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:19]([C@H:21]3[CH2:25][NH:24][C:23](=[O:34])[CH2:22]3)[CH3:20])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cc(-c2ccccc2)cc2ncccc12
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccccc2)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 21 h
Yield: 17.8 %

Procedure:
30 mg of 7-Phenylquinolin-5-ol, 32.5 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one and 150 mg of triphenylphosphine were dissolved in 3 mL of DCM. 125.5 mg of Di-tertbutyl-azodicarboxylate (DBAD) was added and the mixture stirred for 21 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash column chromatography (FCC) (20 SiO2; cyclohexane→cyclohexane:ethylacetate:MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 2 mL of trifluoroacetic acid (TFA) and heated 45 min at 150° C. in the microwave. The mixture was purified with rpHPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 8 mg of Example 1 as solid. Analysis: HPLC-MS: Rt=1.21 min (method D), M+H=333.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.CO/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].O.P(Cl)(Cl)(Cl)=O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: CO/C=C/C(=O)OC
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 22 h
Yield: 50.9 %

Procedure:
0.31 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.28 g of methyl trans-3-methoxyacrylate, 36 mg of water and 6 mL of acetonitrile were mixed, then, 164 mg of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 22 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.21 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 51%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[CH:21])[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:22])[CH3:6])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[C:21][C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=3)[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:22])[CH3:6])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCC1(COc2ccc(OC(C)(C)C(=O)OCC)c(C)c2)CC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC2(CC#Cc3ccc(OC(F)(F)F)cc3)CC2)cc1C

Procedure:
In analogy to the procedure described in example 24E), reaction of 2-methyl-2-[2-methyl-4-(1-prop-2-ynyl-cyclopropylmethoxy)-phenoxy]-propionic acid ethyl ester (example 35I]) and 1-iodo-4-trifluoromethoxybenzene gave the title compound as light yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c(-c3nsc(COS(C)(=O)=O)n3)cn(CC3CCCCC3)c12
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To a cooled solution (ice/methanol bath) of [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (2.3 g, 6.4 mmol) in dichloromethane (150 ml) was added methanesulfonyl chloride (0.595 ml, 7.68 mmol) and triethylamine (1.16 ml, 8.32 mmol) sequentially. The reaction was allowed to stir for 10 min and then poured into a separating funnel. The organics were washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford methanesulfonic acid 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (2.9 g, 6.7 mmol) which was used without further purification.