Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH3:19].[OH-].[Na+].Cl>CCO>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])/[CH:17]=[CH:7]/[C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])=[CH:12][C:11]=1[CH3:19]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: Cc1ncsc1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)/C=C/c2scnc2C)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Commerically available 4-methylthiazole-5-carbaldehyde (0.59 g, 4.6 mmol) and 4′-hydroxy-3′-methylacetophenone (0.7 g, 4.6 mmol) were dissolved in 10 mL of absolute EtOH. The solution was cooled with an ice-water bath, and NaOH (0.36 g, 9.0 mmol) was added. The reaction mixture was stirred for 18 h at room temperature. Upon completion, the reaction mixture was acidified to pH=4-5 with 1 M HCl. The resulting orange precipitate was filtered out, washed with an additional 5 mL of water, and dried under air. The resulting ((E)-1-(4-hydroxy-3-methylphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (1.03 g, 87%) was submitted to the next step without further purification. MS (EI) for C14H13NO2S: 260 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1CCCCC1

Procedure:
The title compound was prepared from N-(t-butoxycarbonyl)D-prolinal and piperidine using the procedure detailed in example 200; MS (ES+), m/e 269 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C1COCC1>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a stirred solution of 2-bromo-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridin-4-amine (Description 59) (487 mg, 1.461 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added LiHMDS (1M solution in THF) (1.608 mL, 1.608 mmol) and 3-chlorobenzenesulfonyl chloride (0.226 mL, 1.608 mmol). The reaction mixture was warmed to RT under a nitrogen atmosphere for ca. 1 h and was then partitioned between ethyl acetate and water (ca. 30 mL each). The aqueous layer was separated and re-extracted with ethyl acetate (ca. 30 mL) and the combined organic layer passed through a phase separator and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane afforded the title compound (320 mg). LCMS (A) m/z: 508/510 [M+1]+, Rt 1.60 min (acidic).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=[O:7].[CH2:33](O)[CH3:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:33]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:3][CH:2]([CH3:32])[CH3:1])[CH3:34]
Reactant: CCO
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 55 %

Procedure:
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (183 mg) was taken up in 40 mL of dry CH2Cl2 and at 0° C. ethanol (0.5 mL, 5 eq) was added followed by N,N-dimethylaminopyridine (0.1 eq, 5 mg) and finally EDCI (209 mg, 5 eq). The resulting solution was stirred from 0° C. to room temperature overnight. Additional CH2Cl2 (100 mL) was added and the mixture was washed with 0.5N HCl (2×50 mL), saturated NaHCO3 (2×50 mL) and finally with brine (1×50 mL). The organic layer was dried over Na2 SO4, filtered and evaporated to dryness. Recrystallization from ethyl acetate and petroleum ether gave (3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid ethyl ester as a white solid (Yield: 108 mg, 55%), MS: 470 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](Cl)=[C:30]3[C:29]([CH3:37])=[N:28]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][N:32]=[C:31]2[N:27]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:39][CH:38]=3)[N:28]=[C:29]([CH3:37])[C:30]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: O=C1Nc2ccccc2CN1c1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N5Cc6ccccc6NC5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a round bottom flask were added 3-(3-fluoro-4-hydroxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (19 mg, 0.074 mmol) and DMF (0.7 mL). 1-(4-Methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (25.4 mg, 0.088 mmol), prepared according to the procedure of Example 43, Step E, was added followed by potassium carbonate (12.2 mg, 0.088 mmol) and a 1 M solution of potassium t-butoxide in THF (0.088 mL, 0.088 mmol). The mixture was stirred at 110° C. for 4 hours under nitrogen. The reaction was cooled to room temperature and the reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with a second portion of ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give 29.8 mg of brown oil. The crude oil was triturated with a dichloromethane:ether mixture and the resulting solid was filtered and dried to afford the desired product as a tan solid (17.6 mg, 47%). LRMS (APCI pos): m/e 510.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16]CCO3)[CH2:11][CH2:10]2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([Cl:34])=[CH:23][N:22]=1.Cl>CC(O)C>[Cl:34][C:24]1[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:26][C:21]([NH:4][C:3]2[C:2]([CH3:1])=[CH:8][C:7]([CH:9]3[CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]3)=[C:6]([CH3:19])[CH:5]=2)=[N:22][CH:23]=1
Reactant: Cc1cc(C2CCC3(CC2)OCCO3)c(C)cc1N
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (86 mg, 0.33 mmol) and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (104 mg, 0.43 mmol) in iPrOH (3 mL) was treated with HCl (82 μL, 4N in dioxane, 0.33 mmol) and heated to 125° C. in a sealed tube for 14 h. After cooling down to room temperature, the mixture was concentrated and was treated with acetone (2 mL) and HCl (330 μL, 4N in dioxane) at room temperature for 5 h. The mixture was then treated with saturated NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, concentrated and purified by flash column chromatography (silica gel, 0%-100% EtOAc in hexanes gradient) to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanone as white solid; ESMS m/z 425.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:22]=S.N=C=N>O1CCCC1>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:22]([NH:21][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: N=C=N
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(Nc4ccccc4)nc23)[C@H]2C=C[C@@H]1C2

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100 mg, 0.5 mmol), isothiocyanatobenzene (60 L, 0.5 mmol), and PS-carbodiimide (769 mg, 1.01 mmol) were heated overnight at 70° C. in a sealed tube with tetrahydrofuran (10 mL). The solids were removed by filtration and the filtrate was concentrated. The organics were purified by reverse phase chromatography (Gilson) to afford, following neutralization and concentration, the title compound as a yellow solid (21%). 1H NMR (d-4 methanol): 7.73 (m, 3H), 7.29 (m, 2H), 6.98 (m, 1H), 6.44 (m, 1H), 6.40 (m, 1H), 5.31 (m, 1H), 4.88 (m, 3H), 2.98 (s, 1H), 2.89 (s, 1H), 2.73 (m, 1H), 2.37 (m, 1H), 1.57 (m, 1H), 1.30 (m, 2H). MS: 394.9 (M+H). HPLC retention time: 2.33 minutes (G Method).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][SH:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Cl>O.CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][S:5][NH:18][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)(=[O:17])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: COCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSNS(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
3.6 of 2-methoxyethyl-mercaptan is added dropwise to a mixture of 3.5 g of 55% sodium hydride and 80 ml of dimethylformamide. To this mixture 8.0 of 2-fluorophenylsulfonamide are added. The reaction mixture is stirred for 3 hours at a temperatur of 115°-120° C. After cooling the mixture is poured into water. To this mixture 10% of hydrochlorid acid are added, and the product is extracted with ethyl acetate. The organic phase is evaporated and the residue is purified by chromatography. Yield: 6.7 g of 2-methoxyethylthio-phenylsulfonamide, m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[N:20]=[CH:19][N:18]([CH2:21][CH2:22][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[N:17]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([S:23]([CH2:22][CH2:21][N:18]3[CH:19]=[N:20][C:16]([CH3:15])=[N:17]3)(=[O:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1ncn(CCS(=O)(=O)c2ccc(C(=O)O)cc2)n1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1ncn(CCS(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)n1

Procedure:
60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)ethylsulfonyl)benzamide. MS (Q1) 482.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:36]=[C:25]([C:26]5[CH:27]=[C:28]([S:32]([NH2:33])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) (162 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (dichloromethane) as a light yellow solid (170 mg, 68%). MS (ISN) 501.1 [(M−H)−]; mp 231° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:30][CH2:29][C:24]3(OCC[O:25]3)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1.Cl.[OH-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-6-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared according to a procedure similar to Example 1) (420 mg, 0.9771 mmol) in tetrahydrofuran (10 mL) was added HCl (4.886 mL of 2 M, 9.771 mmol). The resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was diluted with water (100 mL), made basic with 2.5 N aqueous sodium hydroxide, and extracted three times with dichloromethane (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-amino-6-chloro-N-(4-(4-oxopiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid which was used without further purification. MS (ES+) 386.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[CH2:24]([CH:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)[CH2:25][CH3:26].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>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:30]4[CH2:31][CH2:32][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CCCC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 25 °C
Yield: 109 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.301 g, 0.00124 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol). 4-Propylcyclohexanol (0.211 g, 0.00148 mol) and triphenylphosphine polymer-bound (1.07 g, 0.00198 mol) were added and the mixture was stirred at room temperature. Diisopropyl azodicarboxylate (0.390 mL, 0.00198 mol) was then added and the mixture was stirred for 2 days at room temperature. The mixture was filtered through CELITE™, concentrated and purified by flash chromatography (0-30% EtOAc in methylene chloride) to give 0.4942 g of to the title product (109% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)ccn1
Temperature: 80 °C
Yield: 35.3 %

Procedure:
N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (55 mg, 0.36 mmol), 0.3 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (31 mg, 35%). ESI-MS m/z calc. 439.1. found 440.3 (M+1)+. Retention time 2.12 minutes.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]>Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1cccc(C(=O)c2ccccc2)c1
Agent: Br
Product: O=C(c1ccccc1)c1cccc(O)c1

Procedure:
0.1 mole of the 3-methoxybenzophenone thus obtained is heated under reflux for 9 hours in 100 ml of 48% hydrobromic acid. When the hydrolysis is finished the product obtained is recrystallised in a mixture of equal volumes of water and alcohol. Yield: 78%. Melting point of the product obtained: 118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH3:32])[CH3:27]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13]CCN(C)C)[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Reactant: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 80 °C
Reaction time: 0.15 h
Yield: 9 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (200 mg, 0.36 mmol) and 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 0.43 mmol) in DMF (10 mL) were added CuI (18 mg, 0.08 mmol) and Pd(PPh3)4 (14 mg, 0.014 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (13 mg, 9%). LCMS: (M+H)+=472; 1H NMR (300 MHz, CD3OD): δ 9.11 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 7.38 (d, 1H, J=8.7 Hz), 6.85 (t, 1H, J=74.1 Hz), 4.85-4.78 (m, 2H), 4.65-4.60 (m, 1H), 3.34-3.32 (m, 2H), 2.89 (s, 6H), 2.50-2.40 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H).