Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].O.C(=O)(O)[O-].[Na+].[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14]=[C:15]2[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH:15]2[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1
Reactant: Fc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (1.9 g, 6.6 mmol) in methanol (40 mL) from step 2 was cooled to 0° C. and sodium borohydride (0.6 g, 17 mmol) was added in small portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with ethyl acetate (20 mL) and concentrated to yield a reddish-yellow residue which was taken up in ethyl acetate (100 mL), water (30 mL), and saturated sodium bicarbonate (30 mL). After stirring for 15 min, it was transferred to a separatory funnel, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 5-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale-yellow solid. MS (ESI pos. ion) m/z: 296 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][CH2:5]1.C(O[C:16]1[O:17][CH2:18][C:19](=[O:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[O:26]=[C:19]1[CH2:18][O:17][C:16]([NH:10][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:11])[F:12])[CH2:5][CH2:6]2)=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C1=C(OCC)OCC1=O
Reactant: NN1CCN(CC(F)(F)F)CC1
Solvent: CCO
Product: CCOC(=O)C1=C(NN2CCN(CC(F)(F)F)CC2)OCC1=O
Reaction time: 2 h

Procedure:
To a solution of 4-(2,2,2-trifluoroethyl)piperazine-1-amine (4.72 g, 25.8 mmol) in ethanol (43 mL), ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (4.70 g, 23.5 mmol) which similarly prepared according to the procedure described in the Example 74, Third step was added at ambient temperature. The mixture was stirred for 2 h. The precipitate was collected by filtration, washed with diethyl ether and hexane then dried to afford ethyl 4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-carboxylate as solid (5.64 g, y. 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][N:7]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)COCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
(6-Chloropyridin-3-yl)methanol (1.0 g, 6.97 mmol) was dissolved in THF (20 mL), potassium tert-butoxide (0.860 g, 7.66 mmol) was added and the mixture stirred at room temperature. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.78 g, 7.66 mmol) was added dropwise with ice cooling and then the mixture stirred at room temperature for 2 h. EtOAc (50 mL) and water (50 mL) were added, the organic layer was separated and the aqueous layer neutralised to pH 6. The aqueous layer was then further extracted with EtOAc (3×20 mL), combined organic layers were dried over sodium sulfate and concentrated to yield a yellow solid. This was purified by FCC, eluting with a gradient of 0-50% EtOAc in heptane to afford the title compound as a colourless oil (0.537 g, 34%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.30 (1H, d), 7.61 (1H, dd), 7.30 (1H, d), 4.61 (2H, s) and 3.82 (2H, q).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:9][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:11]([F:10])([F:22])[F:23])[CH:14]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2cccc(OC(F)(F)F)c2)cc1F
Yield: 34.8 %

Procedure:
The title compound (0.5 g) was prepared from 4-Bromo-2-fluoroaniline (1 g, 5.3 mmol) and 3-(trifluoromethoxy)phenylboronic acid (1.4 g, 6.8 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.62 (d, J 8, 1H), 7.53 (s, 1H), 7.48 (t, J 8, 1H), 7.42 (dd, J 2, 9.1, 1H), 7.28 (dd, J 2, 8.3, 1H), 7.23 (d, J 11, 1H), 6.82 (t, J 8.5, 1H), 5.40 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@:6]([C:12]([N:14]1[C@@H:18]([CH3:19])[CH2:17][CH2:16][C@H:15]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:41][C:40]([C@@H:42]5[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]5[C:50](=[O:61])[C@@H:51]([NH:56][C:57](=[O:60])[O:58][CH3:59])[C@H:52]([O:54][CH3:55])[CH3:53])=[N:39][CH:38]=4)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:13])([C@@H:8]([CH3:11])[O:9][CH3:10])[NH2:7])=[O:4].[Cl:62]N1C(=O)CCC1=O>CN(C=O)C>[Cl:62][C:38]1[N:39]=[C:40]([C@@H:42]2[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]2[C:50](=[O:61])[C@@H:51]([NH:56][C:57](=[O:60])[O:58][CH3:59])[C@H:52]([O:54][CH3:55])[CH3:53])[NH:41][C:37]=1[C:34]1[CH:35]=[CH:36][C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[NH:21][C:20]([C@@H:15]4[CH2:16][CH2:17][C@H:18]([CH3:19])[N:14]4[C:12](=[O:13])[C@@:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])([C@@H:8]([CH3:11])[O:9][CH3:10])[NH2:7])=[N:24][CH:23]=3)=[CH:30][CH:29]=2)=[CH:32][CH:33]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@](N)(NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2nc(Cl)c(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@](N)(NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Temperature: 45 °C
Yield: 4.6 %

Procedure:
To a solution of methyl {(2S,3R)-1-((2S,4S)-2-(5-(4′-(2-((2S,5S)-1-((2S,3R)-2-(methoxycarbonylamino)-O-methyl-L-threonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-yl}carbamate (0.12 g, 0.15 mmol) in DMF (1.5 mL) was added N-chlorosuccinimide (0.05 g, 0.38 mmol). The resulting solution was heated to 45° C. for 3 h and cooled to room temperature. The reaction solution was purified by preparative HPLC (Gemini C18, 20-75% MeCN/H2O (0.1% TFA)). The desired fractions were combined and lyophilized to provide methyl {(2S,3R)-1-((2S,4S)-2-(4-chloro-5-(4′-(2-((2S,5S)-1-((2S,3R)-2-(methoxycarbonylamino)-O-methyl-L-threonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-yl}carbamate (0.006 g, 5%).
Reaction SMILES: [CH3:1]OC1C=C(OC)C=CC=1C(Cl)=O.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25]N=2)[CH:19]=[CH:18][C:16]=1[NH2:17].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:1]=2)[CH:19]=[CH:18][C:16]=1[NH:17][C:50]([NH:49][C:47](=[O:48])[C:40]1[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:39]=1[O:38][CH3:37])=[S:51]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][CH2:6][C@@H:7]([N:11]1[CH:15]=[C:14]([C:16](OCC)=[O:17])[N:13]=[CH:12]1)[C@@H:8]([OH:10])[CH3:9].[OH-].[NH4+:26]>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][CH2:6][C@@H:7]([N:11]1[CH:15]=[C:14]([C:16]([NH2:26])=[O:17])[N:13]=[CH:12]1)[C@@H:8]([OH:10])[CH3:9]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn([C@H](COc2ccc(Cl)c(Cl)c2)[C@H](C)O)cn1
Agent: [OH-]
Solvent: COCCOC
Product: C[C@H](O)[C@@H](COc1ccc(Cl)c(Cl)c1)n1cnc(C(N)=O)c1

Procedure:
A mixture of ethyl 1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxylate (0.23 g), 28% ammonium hydroxide (12 mL) and 1,2-dimethoxyethane (6 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient elution; 20:1 to 10:1 chloroform-methanol) to give the product, which was recrystallized from 1:5 n-hexane-ethyl acetate (12 mL) to give 1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide (81) (0.13 g).
Reaction SMILES: C[C:2]1([CH3:20])[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[C:4]([C:17](O)=O)[CH2:3]1.[OH2:21]>>[CH3:7][C:6]1[CH:20]=[CH:2][C:3](=[O:21])[C:4]2[C:5]=1[C:8]1[C:16](=[CH:15][CH:14]=[CH:13][C:9]=1[CH3:10])[CH:17]=2
Reactant: O
Reactant: CC1(C)C=CC(c2ccccc2C(=O)O)=C(C(=O)O)C1
Product: CC1=C2C(=Cc3cccc(C)c32)C(=O)C=C1
Temperature: 60 °C

Procedure:
4,4-Dimethyldiphenic acid (20.0 g, 74.0 mmol) was charged with polyphosphoric acid (83.4 g) at room temperature. The mixture was heated in an oil bath at 120°-121° C. for 6.5 hr until decarboxylation was over (no gas evolved). The reaction mixture was cooled down to 60° C., diluted with water (150 mL) then cooled down to room temperature. The precipitate was filtered off, washed with water, 10% sodium bicarbonate solution until the filtrate became colorless, extracted with 25% solution of ethyl acetate in hexane and dried over magnesium sulfate. Evaporation of the solvents gave the crude ketone which was purified by short path chromatography (5% ethyl acetate in hexane). This afforded 10.8 g (70.4%) of 4,5-dimethylfluorenone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[N:43][CH:42]=[CH:41][N:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[N:43][CH:42]=[CH:41][N:40]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J17) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (350 mg, 61%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:13]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2)cc1OC
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc(OC)c(OC)c1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, 296 mg of sodium hydride was added to an N,N-dimethylformamide solution (30 ml) of 1.99 g N-(3,4-dimethoxyphenyl)benzene sulfonamide and stirred at room temperature for 30 minutes, and then 0.75 ml of ethyl bromoacetate was added thereto and stirred for 2 hours. The reaction liquid was poured into ice water, acidified by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography using ethyl acetate:n-hexane (1:2) as the elution solvent, thereby obtaining 2.47 g of ethyl [(3,4-dimethoxyphenyl)(phenylsulfonyl)amino]acetate as a pale yellow oily substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH2:11])(=[O:10])[CH:8]=[CH2:9]>CCO>[O:10]([CH2:6][CH2:5][CH3:4])[CH2:7][CH2:8][CH3:9].[N:1]1([CH2:9][CH2:8][C:7]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=CC(N)=O
Solvent: CCO
Product: CCCOCCC
Product: NC(=O)CCN1CCCCC1
Yield: 75 %

Procedure:
A solution of piperidine, 4-(diphenylmethylene) (0.10 mole) and acrylamide (8.95 g, 0.062 mole) in EtOH (50 ml) was refluxed overnight. This reaction mixture was filtered and concentrated. The resulting while solid residue was dissolved in CHCl3, washed with H2O (3×150 ml), dried (Na2SO4) and the solvent removed to give thick yellow oil. Crystallization from CH2Cl2 --i--Pr2O afforded 29.01 g (75%) of 1-piperidinepropanamide, 4-(diphenylmethylene)-; mp 105°-7° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:47])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)=[CH:31][C:30]=1[CH3:48].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:48][C:30]1[CH:31]=[C:32]([NH:35][C:36](=[O:47])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=2)[CH:33]=[CH:34][C:29]=1[O:28][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2ccc(Nc3nccc(-c4cccnc4Cl)n3)cc2)CC1
Reactant: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1Oc1ncccc1-c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2)n1
Temperature: 130 °C

Procedure:
To 4-(2-chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (35 mg, 0.092 mmol), N-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)benzamide (27 mg, 0.092 mmol) and Cs2CO3 (60 mg, 0.18 mmol) was added DMSO (0.6 mL). The mixture was heated overnight at 130° C. The crude material was purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound as a light yellow solid after aqueous workup. MS m/z=640 [M+1]+ Calc'd for C35H32F3N7O2: 639.69.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Br[CH2:6][C:7]#[C:8][CH2:9][N:10]([CH3:15])[C:11](=[O:14])[O:12][CH3:13]>>[CH3:13][O:12][C:11](=[O:14])[N:10]([CH2:9][C:8]#[C:7][CH2:6][N:1]1[CH2:4][CH2:3][CH2:2]1)[CH3:15]
Reactant: COC(=O)N(C)CC#CCBr
Reactant: C1CNC1
Product: COC(=O)N(C)CC#CCN1CCC1
Reaction time: 1 h

Procedure:
A solution of methyl[4-(diethylamino)-2-butynyl]- methyl-carbamate (4.2 g, 0.02 mol) (Example 1i) in anhydrous diethyl ether (50 ml) is added dropwise at room temperature to a stirred solution of cyanogen bromide in anhydrous diethyl ether (40 ml). The mixture is allowed to stand for 12 hours and the diethyl ether layer is separated, washed with water (40 ml), dried over magnesium sulfate, and concentrated. The resulting oil is then purified by bulb to bulb distillation under high vacuum to give methyl N-(4-bromo-2-butynyl)-N-methylcarbamate as a ight yellow oil. Azetidine (2 g, 0.032 mol) is added to a stirred solution of methyl N-(4-bromo-2-butynyl)-N-methylcarbamate (3.6 g, 0.016 mol). The mixture is kept at room temperature for one hour and then filtered. The filtrate is concentrated and the resulting oil purified by bulb to bulb distillation under high vacuum to give a light yellow oil. NMR(CDCl3): 4.10 (brs, 2H); 3.7 (s, 3H); 3.39 (brs, 2H); 2.94 (s, 3H); 2.45 (brs, 4H).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:9]1[O:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=1
Reactant: Oc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cc2ncccc2o1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A sealed pressure flask was charged with 2-bromopyridin-3-ol (10.0 g, 57.5 mmol), ethynyltrimethylsilane (15.9 ml, 115 mmol), copper (I) iodide (1.09 g, 5.75 mmol), bis(triphenylphosphine)palladium(II) chloride (2.02 g, 2.87 mmol) and 7.5 mL of dioxane. Ethynyltrimethylsilane (15.9 ml, 115 mmol) and TEA (40.0 ml, 287 mmol) were added, the vial was flushed with nitrogen, and the reaction was stirred at 50° C. for 18 h. The reaction was concentrated and purified via column chromatography (gradient elution 0-40% EtOAc:Hex) to afford 2-(trimethylsilyl)furo[3,2-b]pyridine as a brown oil. MS Found M+H+=192.3
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1>Cl>[Cl:1][C:2]1[C:3]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Cl)cn1
Agent: Cl
Product: Nc1cc(NCC2CCNCC2)c(Cl)cn1
Yield: 86.8 %

Procedure:
Benzyl 4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.52 g, 1.12 mmol) was refluxed in 6M HCl (20 mL) for 2 hr. The volatiles were removed in vacuo and the residue was dissolved in MeOH and adsorbed onto Isolute SCX-II acidic resin. The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated to give crude 5-chloro-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.234 g, 96%). LCMS (4) Rt=0.51 min; m/z (ESI+) 241 (MH+). Di-tert-butyl dicarbonate (0.21 g, 1 eq.) in dichloromethane (1 mL) was added dropwise to 5-chloro-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.228 g, 0.95 mmol) and triethylamine (0.40 ml, 3 eq.) in dichloromethane (6.5 mL). The solution was stirred at room temperature for 2 hr. Solvents were evaporated and the crude product was purified by preparative thin layer chromatography, eluting with 8% MeOH, 1% NH3, 91% dichloromethane, to give tert-butyl 4-((2-amino-5-chloropyridin-4-ylamino)methyl)piperidine-1-carboxylate (109 mg, 34%) as a white powder.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].[Br:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:27]>C(O)CCC.ClCCl>[Br:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[N:27]1[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cccc2cc(Br)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCO
Product: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (D1) as an oil (2.6 g, 8.5 mmol, 49%);
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C1COCC1>[C:21]([O:24][CH2:25][C:26](=[O:27])[CH2:9][C:4]1[O:3][C:2]([CH3:10])([CH3:1])[O:7][C:6](=[O:8])[CH:5]=1)(=[O:23])[CH3:22]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC(=O)OCC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)CC1=CC(=O)OC(C)(C)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (20 g, 141 mmol) in dry THF (400 mL) was cooled to −78° C. To this solution was slowly added a LiHMDS (1M-THF, 160 mL, 160 mmol). The resulting solution was maintained at −78° C. with stirring for 30 min. To the reaction mixture was added acetoxy acetylchloride (17 mL, 160 mmol) and the resulting mixture was maintained at −78° C. for at 1 h. The reaction was then allowed to slowly warm to rt and stir for an additional 1 h. The reaction was then quenched with addition of a 1N solution of ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate (5×). The organics were combined, dried, and concentrated in vacuo. The crude product was purified using a medium pressure liquid chromatography biotage system. Elution with hexanes-ethyl acetate (3:1) gave 13.1 g (38%) of a red-brown oil. The product looks clean by NMR. 1H NMR (300 MHz, CDCl3) δ 5.42 (s, 1H), 4.75 (s, 2H), 3.41 (s, 2H), 2.22 (s, 3H), 1.75 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[SH:11].Br[C:13]1[O:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=1>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[S:11][C:13]1[O:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Fc1cc(F)c(F)c(S)c1F
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2c(F)c(F)cc(F)c2F)c1

Procedure:
In an open flask, cuprous oxide (1.95 g., 13.7 mmoles) was combined with 2,3,5,6-tetrafluorothiophenol (5.0 g., 27.4 mmoles) in 40 ml. of dimethylformamide and heated at 140° C. for 2 hours. The reaction was cooled, 5-bromofuran-3-carboxylic acid (2.62 g., 13.7 mmoles) in 50 ml. of dimethylformamide was added, the reaction mixture refluxed for 2 hours, and product (2.75 g.) isolated according to the procedure of Example 9. Recrystallization from methanol/water gave purified 5-(2,3,5,6-tetrafluorophenylthio)furan-3-carboxylic acid (1.78 g., m.p. 150°-153° C., m/e 292).