Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2C(=CC=CC=2)C=CC1=O.C(N(CC)CC)C.[OH:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:32]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=c1ccc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(=O)oc2cc(OC(=O)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The route shown in Scheme 1 exemplifies synthesis of the coumarin compounds of the present invention. Triethylamine is added to a solution of 7-hydroxy-4-methyl-chromen-2-one (i) and a benzoyl chloride (ii) in THF at room temperature. The reaction mixture is stirred at room temperature overnight and filtered. The filtrate is concentrated to afford a 7-benzoyloxy-4-methyl-coumarin (iii). A mixture of compound (iii) and finely powdered aluminum chloride is heated at 170° C. for 2 hours to afford an 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (iv). A mixture of compound (iv), 2-bromoacetophenone (v), and K2CO3 in CH3CN is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography to afford a pure 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one (vi).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C([NH+](CC)CC)C>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-cyanobenzoate (0.67 mmol), sodium azide (0.13 g, 2.04 mmol), and triethylammonium hydrochloride (0.14 g, 1.03 mmol) in N-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the aqueous layer three times with ethyl acetate. Adjust the pH of the aqueous layer to about 1 using a 1M aqueous hydrochloric acid solution, The aqueous layer is again extracted three times with ethyl acetate, and twice with dichloromethane. The aqueous layer is saturated with sodium chloride and again extracted four times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[CH2:25]([NH2:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>>[O:31]1[C:32]2[CH:33]=[CH:34][C:26]([CH2:25][NH:35][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=3)=[O:21])=[CH:27][C:28]=2[O:29][CH2:30]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Yield: 97.6 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.7 g, 4.3 mmol), 5-methyl-4-nitro-thiophene-2-carboxylic acid (0.6 g, 3.2 mmol), and piperonyl amine (0.5 g, 3.3 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 1 g of 5-methyl-4-nitro-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide. A sample was dissolved in ethyl acetate and filtered through a short column of silica gel to give 5-methyl-4-nitro-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide; mp 181-183° C.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[N:13]([C:14]2[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[CH:18]=2)[C:12]2[N:11]=[C:10]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:39])[C:5]1=[O:40])[CH3:3]>O1CCOCC1.CO>[CH2:2]([CH:4]1[N:13]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[C:12]2[N:11]=[C:10]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:39])[C:5]1=[O:40])[CH3:3]
Reactant: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cnn(COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cn[nH]c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
HCl (2 mL of a 4 N solution in dioxane) was added to a solution of 7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one (Example 342, 49 mg, 0.0893 mmol) in 2 mL of methanol and the resulting solution was stirred at 60° C. for 2 hours. The mixture was concentrated under vacuum and purified by HPLC to give the title compound. 1H-NMR (CDCl3, 400 MHz): δ: 7.90 (s, 1H), 7.75 (s, 1H), 7.50-7.54 (m, 3H), 7.35 (s, 2H), 7.03-7.07 (m, 2H), 4.59-4.61 (m, 1H), 3.46 (s, 3H), 1.98-2.03 (m, 1H), 1.77-1.84 (m, 1H), 0.84 (t, 3H, J=7.4 Hz); LCMS: 418.9 m/z (M+H)+; ret. Time: 3.98 min (Analytical Method C).
Reaction SMILES: [Li][C:2]1([Si](C)(C)C)[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl[C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[CH3:21][O:20][C:18]([CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: COC(=O)Cl
Reactant: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21
Solvent: C1CCOC1
Product: COC(=O)C1CCCc2cc(C)cnc21
Temperature: 25 °C

Procedure:
8-Lithio-5,6,7,8-tetrahydro-3-methyl-8-trimethylsilylquinoline, prepared as in Example 3, is treated with 1 equivalent of methyl chloroformate in THF at -20° C. under nitrogen. After the addition the mixture is allowed to warm to ambient temperature and the solvent removed by evaporation. The residue is dissolved in 2NHCl and washed with ether basified with Na2CO3 and extracted with chloroform. The extracts are dried and evaporated. Distillation of the residue gives the title compound as a pale yellow oil bp 120°/0.25 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[C:11](F)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:9][C:10]1[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Br)c(F)cc1F
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
A mixture of 4-chlorophenol (94.7 mg, 0.74 mmol), methyl 5-bromo-2,4-difluorobenzoate (Preparation 18, 168 mg, 0.67 mmol), and potassium carbonate (277 mg, 2.01 mmol) in dimethyl sulfoxide (3 mL) was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were successively washed with aqueous sodium hydroxide solution (1.0 M, 20 mL), brine (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colourless oil (199 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1nccs1
Temperature: 90 °C
Reaction time: 16 h
Yield: 56.2 %

Procedure:
Commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (10.06 g, 47.7 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (150 mL) and water (25 mL), and 2-bromothiazole (4.40 mL, 48.8 mmol), palladium (II) acetate (535 mg, 2.38 mmol), triphenylphosphine (2.50 g, 9.53 mmol) and potassium carbonate (19.50 g, 141 mmol) were added, followed by stirring at 90° C. for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (300 mL) and ethyl acetate (400 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-20%) to afford the desired compound (6.71 g, yield 56%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=1[O:26][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ccnc12
Yield: 85.2 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-3 using 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 300 mg, 1.44 mmol), 2-fluoro-5-(trifluoromethyl)phenol (389 mg, 2.16 mmol), K2CO3 (596 mg, 4.32 mmol) in CH3CN (4 mL) to afford 432 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.82 (d, J=4.8 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.36 (d, J=7.5 Hz, 1H), 8.11 (d, J=5.7 Hz, 1H), 7.86-7.75 (m, 3H), 6.93 (d, J=4.8 Hz, 1H); MS (m/z): 353.21 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:7][C:8]=1[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34].C1(C)C=CC=CC=1.C(P(CCCC)CCCC)CCC>CCOCC>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:11][CH2:10][CH:9]([C:8]2[O:7][C:6]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:12])=[CH:29][C:28]=1[CH3:34]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Reactant: COC(=O)Cc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 0 °C

Procedure:
A mixture of 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol, (0.18 g, 0.5745 mmol), (4-Hydroxy-2-methyl-phenyl)-acetic acid methyl ester (0.114 g) and toluene (10 mL) and azodicarboxylic dipiperidide (0.19 g, 0.747 mmol) is stirred at −20 deg C. Neat tri-n-butyl phosphine (0.19 mL, 0.747 mmol) is added dropwise and the resulting mixture is allowed to reach room temperature with stirring 18 hr. The mixture is diluted with ether (25 mL) and cooled in ice/water for 30 min. The mixture is filtered, concentrated, and purified via silica gel chromatography eluting with 95:5 hexanes:ethyl acetate to afford the title compound as a thick oil, 0.065 g, 24%. MS M++1 476. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]I>>[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: COC(=O)Cc1ccccc1CI
Product: COC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (2-iodomethylphenyl)-acetic acid methyl ester analogous to Example 310, steps C and D.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:30])[CH2:28][OH:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:28][OH:29])=[CH:25][CH:26]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NC(CO)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2ccc(Cl)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-chloro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(4-chloro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36])#[N:31]>ClCCl>[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:36])#[N:31]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C#N)c3)nn2)cc(OC)c1OC
Yield: 83.7 %

Procedure:
In a similar manner as described for Intermediate 18 (below), 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.10 g, 0.33 mmol), triethylamine (0.10 mL, 0.73 mmol) and 3-cyanobenzoyl chloride (0.059 g, 0.36 mmol) in dichloromethane (10 mL) gave 3-cyano-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.12 g) as a white solid. MS m/z 435 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)OC)c(N)c1

Procedure:
23.9 g (0.1 mol) of dimethyl 2-nitroterephthalate are hydrogenated in a mixture of 100 ml of methanol and 200 ml of tetrahydrofuran with palladium/charcoal at 5 bar and 20° C. After the catalyst has been removed by suction filtering the solvent is evaporated off and the residue is recrystallised from methanol. Yield 18-19 g, yellowish crystals m.p. 130-131° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][C@H:17]2[O:26][CH3:27])=[O:14])=[C:11]([O:31][CH3:32])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[NH2:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:18][C@H:17]2[O:26][CH3:27])=[O:14])=[C:11]([O:31][CH3:32])[CH:10]=1
Reactant: Clc1ncccn1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCNc2ncccn2)C[C@H]1OC
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 35 %

Procedure:
A mixture of 1.17 parts of 2-chloropyrimidine, 5.56 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 2.7 parts of N,N-dimethylacetamide was stirred for 6.5 hours at 90° C. After cooling, a sodium carbonate solution was added. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.4 parts (35%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-(2-pyrimidinylamino)propyl]-4-piperidinyl]benzamide; mp. 158.5° C. (compound 36).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O.CCOC(C)=O.[Cu]I.CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3cncn3)cn2)CC1
Temperature: 100 °C
Yield: 46.4 %

Procedure:
[1-(5-Iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (100 mg, 0.28 mmol), CuI (11 mg, 0.06 mmol), 1,2,4-triazole (29 mg, 0.42 mmol) and K3PO4 (118 mg, 0.556 mmol) were mixed in a 8-mL microwave vial. (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (18 μL, 0.11 mmol) was added to the mixture under argon followed by DMF (2 mL). The reaction was heated at 100° C. overnight. The reaction was then cooled to room temperature and diluted with water (50 mL) and EtOAc (50 mL). The organic layer was collected and dried over MgSO4. The residue was purified by flash chromatography on silica gel (20% EtOAc/Hex to 100% EtOAc) to give [1-(5-[1,2,4]triazol-1-yl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (40 mg, 0.13 mmol, 48%) as a semi-solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].B(Br)(Br)Br.[CH2:18](O)[CH:19]=C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH2:11][CH:18]=[CH2:19])=[O:9]
Reactant: C=CCO
Reactant: COC(=O)c1cc(CBr)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(CBr)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-bromomethyl-2-fluorobenzoate (12.49 g, 50.6 mmol) in methylene chloride (150 mL) at 0° C. is added BBr3 (5.26 mL, 55.62 mmol) slowly, via syringe. The solution is then warmed to room temperature over 2.5 hours, and then is cooled back down to 0° C., and allyl alcohol (103 mL, 1.52 mol) is added dropwise. The solution is then stirred overnight, after which time it is diluted with CH2Cl2 (250 mL), then washed with sat'd aq. NaHCO3 (2×300 mL), brine (150 ml), and dried over MgSO4. Evaporation of solvent yields allyl 5-bromomethyl-2-fluorobenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[C:14](Br)Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[CH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a stirred cold (minus 78° C.) solution of l-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl) pyrrolidine (7.81 g, 22 mmol) in THF (200 mL) was added n-BuLi (1.59 M in hexane, 28 mL, 44 mmol) over 10 min, and the stirring was continued for 2 hr at the same temp. The reaction was quenched by the addition of sat. NH4Cl and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane-AcOEt (10:1, v/v) as eluent to give 4.15 g (97%) 1-(tert-butoxycarbonyl)-2-ethynyl pyrrolidine as a light yellow oil. 1H-NMR (CDCl3) δ 1.48 (9 H, s), 1.82–2.21 (4 H, m), 3.30–3.45 (2 H, m), 4.41–4.52 (1 H, m).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.Cl[C:13]1[S:14][CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C.[Cl-].[Na+].O>[N+:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccsc1-n1cccn1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (2.28 g, 20.3 mmol) and 1H-pyrazole (2.02 g, 29.7 mmol) in DMF (50 ml) was stirred for 30 min. 2-chloro-3-nitrothiophene (2.56 g, 15.6 mmol) was added and the solution was placed into a preheated oil bath at 100° C. After stirring for 1 h, the solution was diluted with brine and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethyl acetate as the eluant to yield impure 1-(3-nitrothiophen-2-yl)-1H-pyrazole. Method [1] Retention time 1.52 min by HPLC (MH+196).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:40]=[C:39]([CH3:41])[O:38][C:37]=1[C:42]([F:45])([F:44])[F:43])(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:40]=[C:39]([CH3:41])[O:38][C:37]=4[C:42]([F:45])([F:44])[F:43])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cc1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)c(C(F)(F)F)o1
Agent: Cl
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4[nH]cnc34)c2F)c(C(F)(F)F)o1
Reaction time: 2 h
Yield: 85 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methyl-2-(trifluoromethyl)furan-3-sulfonamide (12 mg, 0.020 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 9 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-5-methyl-2-(trifluoromethyl)furan-3-sulfonamide (percentage yield: 85%), was obtained.