Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:44])C)=O)(C)(C)C.[Cl:45][CH2:46]Cl>Cl.C(OCC)C>[ClH:45].[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH:9]([CH3:44])[NH:8][CH:13]([CH3:46])[CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: ClCCl
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CC(C)NC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.250 g, 0.414 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl in diethyl ether (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the solid was dried in a vacuum oven for 24 hours at 50° C. to give 6-acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.120 g, 38.1%). 1H NMR δ (400 MHz, DMSO-d6) 9.51 (m, 2H), 9.0 (m, 1H), 8.97 (s, 1H), 8.08 (d, J=2.7 Hz, 1H), 7.84 (dd, J=9.3 Hz, 1H), 7.78 (m, 1H), 5.80 (m, 1H), 3.35 (d, J=11.5 Hz, 2H), 3.35 (m, 2H, 2.75 (dd, J=12.2, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 2.19 (m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.57 (m, 2H), 1.29 (d, J=6.6 Hz, 6H). MS (APCI); M++1: Calc'd, 476.3, Found 476.1. Anal. Calc'd for C26H33N7O2 2.70 HCl, 0.10 H2O: C, 54.23, H, 6.28, N, 17.03. Found: C, 54.60; H, 6.68; N, 16.57.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)=[O:12])#[N:2]
Reactant: N#Cc1cccc(OCCCC(=O)O)c1
Reactant: N#Cc1ccc(N)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)CCCOc2cccc(C#N)c2)cc1
Reaction time: 0.03 h

Procedure:
100 mg (0.49 mmol) of 4-(3-cyanophenoxy)butyric acid and 50 mg (0.49 mmol) of triethylamine were stirred in dimethylformamide under cooling with ice. 53 mg (0.49 mmol) of ethyl chloroformate was added to the resultant mixture. After stirring for 2 minutes, 58 mg (0.49 mmol) of p-aminobenzonitrile was added to the reaction mixture. The temperature was elevated to room temperature, and they were stirred overnight. 1 N hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[Al](C)C.CCCCCC.[O:19]=[C:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([NH:34][C:35]2[C:39]3=[N:40][CH:41]=[CH:42][CH:43]=[C:38]3[O:37][C:36]=2[C:44](OC)=[O:45])=[O:33])[CH2:28][CH2:27]1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:44]([C:36]2[O:37][C:38]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[C:35]=2[NH:34][C:32]([C@H:29]2[CH2:30][CH2:31][C@H:26]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][C:20]3=[O:19])[CH2:27][CH2:28]2)=[O:33])=[O:45])=[N:3][CH:4]=1
Reactant: COC(=O)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)c2oc3cccnc3c2NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)nc1
Reaction time: 0.5 h

Procedure:
2-Amino-5-methylpyridine (81 mg) is dissolved in chloroform (5 ml). After adding 0.98 M trimethyl aluminum-hexane solution (763 μl) under ice-cooling, the reaction solution is stirred under ice-cooling for 10 minutes, and then at room temperature for 0.5 hours. To the resulting reaction solution is added methyl 3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxylate (150 mg) obtained in Reference Example 79, and the mixture is stirred at room temperature for 2 hours and at 50° C. under heating for 5 hours. To the reaction solution is added 10% hydrochloric acid (3 ml) under ice-cooling, and the mixture is stirred at room temperature for 0.5 hours. The reaction solution is then neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in diethyl ether, and collected by filtration to give the title compound (110 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[O:17])[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccc(CC(=O)O)cc1
Product: O=C(O)Cc1ccc(NC(=O)C2CCC2)cc1

Procedure:
(4-Cyclobutanecarbonylaminophenyl)-acetic acid was prepared as described in Example 3 from 7.0 g (0.0464 mol) of (p-aminophenyl)-acetic acid and 6.6 g (0.0557 mol) of cyclobutanecarboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=1.Br[C:23]1[N:24]=[C:25]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C1(C)C(C)=CC=CC=1.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>[CH2:39]([N:36]1[CH2:35][CH2:34][N:33]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:32]=[C:23]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[N:24]=2)[CH2:38][CH2:37]1)[CH3:40]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)nc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(OC)nc3)cc3ccccc23)CC1
Yield: 61.3 %

Procedure:
2-Methoxy-5-tributylstannylpyridine (1.41 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.57 g) obtained in Example 28-2 were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.10 g) in xylene in nitrogen atmosphere for 30 min. After cooling, the reaction solution was filtered and extracted in 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate twice. The resulting aqueous layer was adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.38 g of the free compound of the title compound as a pale brown powder.
Reaction SMILES: [CH2:1]([C:11]1[O:12][CH2:13][CH2:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>>[CH2:16]([O:18][Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:11]1[O:12][CH2:13][CH2:14][N:15]=1)[CH3:17]
Reactant: C=CCCCCCCCCC1=NCCO1
Reactant: CCO[SiH](OCC)OCC
Product: CCO[Si](CCCCCCCCCCC1=NCCO1)(OCC)OCC

Procedure:
wherein 2-(9-decenyl)-1,3-oxazoline is reacted with triethoxysilane to form 2-[10-(triethoxysilyl)decyl]-1,3-oxazoline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].[NH2:43][C:44]1[CH:45]=[CH:46][C:47](Cl)=[N:48][CH:49]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:47]3[CH:46]=[CH:45][C:44]([NH2:43])=[CH:49][N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Nc1ccc(Cl)nc1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccc(N)cn3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 5-amino-2-chloropyridine.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH:40]([OH:45])[C:41]([O:43][CH3:44])=[O:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH:40]([OH:45])[C:41]([O:43][CH3:44])=[O:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)O
Reactant: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC
Yield: 25.1 %

Procedure:
To a solution of 30 mg of 2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid and 42 mg of methyl(2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride in 3 ml of N,N-dimethylformamide were added successively 0.023 ml of diphenylphosphoryl azide and 0.040 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume; Rf2 =0.31) to obtain 14 mg of methyl (2RS,3S)-3-{N-[2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]=[O:12])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)C(=O)OC(C)(C)C

Procedure:
To a solution of tert-Butyl N-(tert-butoxycarbonyl)-L-homoserinate (1.00 g, 3.63 mmol) in dichloromethane (50 mL) was added at r.t. pyridine (0.88 mL, 10.9 mmol) and Dess-Martin-periodinane (2.31 g, 5.45 mmol). After 90 min the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% sodium thiosulphate solution (30 mL), saturated sodium bicarbonate solution (40 mL), and brine (40 mL). The combined aqueous layers were extracted with ethyl acetate (50 mL) and the combined organic layers were dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:24])[CH2:16][S:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(O)C>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH:15]([OH:24])[CH2:16][S:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CN(C)CCCSCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CN(C)CCCSCC(O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Sodium borohydride (3.2 g) was added in portions at 0° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)-propylthio]ethanone (16 g, prepared by basification of the hydrochloride salt obtained in a similar manner to that described in Example 7) in methanol (200 ml) then the mixture was stirred at ambient temperature for 7 days and diluted with water (350 ml). The product was extracted into dichloromethane (4×100 ml) and the extracts washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml), dried over sodium sulphate and the solvent removed in vacuo to leave a green oil. The oil was resolved via preparative scale chiral high performance liquid chromatography to give (-)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3 -(dimethylamino)propylthio]ethanol as an oil (3.5 g), [α]rtD =-8.615° (C=1;ethanol) and (+)-1-[1-(3 4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino) propylthio]ethanol as an oil (3.4 g), [α]rtD =+9.740° (C=1; ethanol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C(OC(C1C=NN(C2N(COCCOC)C3C=C(Cl)C([N+]([O-])=O)=CC=3N=2)C=1)=O)C.[Cl-].[NH4+].CC(C)=O>[Zn].O>[NH2:26][C:24]1[C:23]([Cl:27])=[CH:22][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:25]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: CCOC(=O)c1cnn(-c2nc3cc([N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Yield: 86 %

Procedure:
1-[5-Amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester. To a solution of 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate D from Example 40) (7.88 g, 18.6 mmol), ammonium chloride (14.9 g, 0.279 mol), acetone (75 mL), and water (15 mL) at 0° C. was added portion-wise zinc dust (12.2 g, 0.186 mol). The reaction mixture was removed from the ice bath and after 15 min, the reaction mixture was filtered through Celite®/diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated and the remainder was partitioned between EtOAc (300 mL) and saturated aqueous sodium bicarbonate (55 mL). The aqueous layer was further extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine (2×40 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-65% EtOAc/hexanes) to yield the titled compound (6.29 g, 86% yield) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C17H20ClN5O4, 393.1; m/z found, 394.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.83 (d, J=0.6 Hz, 1H), 8.78 (d, J=0.6 Hz, 1H), 8.16 (dd, J=1.9, 0.6 Hz, 2H), 7.63 (s, 1H), 7.54 (s, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.03 (s, 2H), 6.00 (s, 2H), 4.35 (q, J=7.1 Hz, 4H), 4.18 (s, 2H), 4.07 (s, 2H), 3.66-3.60 (m, 4H), 3.49-3.42 (m, 4H), 3.32 (s, 3H), 3.31 (s, 3H), 1.37 (t, J=7.1 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[C:19]([C:21]1[N:25]([CH3:26])[C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:19]([C:21]1[N:25]([CH3:26])[C:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CC(C)NS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1C(F)(F)F
Reaction time: 16 h
Yield: 43.8 %

Procedure:
According to general procedure B, 4-bromo-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (193 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (91 mg, 44%) was provided after purification. MS (ESI) m/z 371. HPLC purity 100.0% at 210-370 nm, 10.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:18][CH2:17][CH:13]([C:14](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:14]([CH:13]3[CH2:17][CH2:18][NH:10][CH2:11][CH2:12]3)[O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc2nc(C3CCNCC3)oc2c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[CH:5][C:4]=1[O:12][CH3:13])=[O:2].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH:1]([C:3]1[C:4]([O:12][CH3:13])=[CH:5][C:6]([O:11][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7][C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: CCOC(=O)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1cc(OC)c(C=O)c(OC)c1
Temperature: 110 °C

Procedure:
To a suspension of 4-formyl-3,5-dimethoxyphenol (22.6 g, 124 mmol) and potassium tert-butoxide (15.3 g, 136 mmol) in dimethylformamide (125 mL) was added ethyl 5-bromovalerate (28.5 g, 136 mmol) in dimethylformamide (125 mL) over a period of 20 min. The mixture was heated at 110° C. for 6 h and concentrated in vacuo. To the obtained product was added ethyl acetate (400 mL) and the mixture was filtered. The filtrate was washed with water (100 mL), 1 N sodium hydroxide (2×50 mL), and brine (3×100 mL), dried (magnesium sulfate), and concentrated in vacuo to 37 g of ethyl 5-(4-formyl-3,5-dimethoxyphenoxy)valerate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[N:14][CH:13]=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([O:16][CH:17]([CH3:18])[CH3:19])=[N:14][CH:13]=[CH:12][N:11]3[C:20]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(I)n1
Reactant: CC(C)Oc1nccn2cc(-c3ccc(F)cc3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(OC(C)C)nccn23)n1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
Pd(OAc)2 (0.233 g, 1 mmol) was added to a degassed mixture of 2-(4-fluorophenyl)-8-isopropoxyimidazo[1,2-a]pyrazine (1.43 g, 5.2 mmol), 4-iodo-2-(methylthio)pyrimidine (Frontier, 1.96 g, 7.8 mmol), Cs2CO3 (2.57 g, 7.8 mmol) and PPh3 (0.54 g, 2 mmol) in DMF (6 mL). The resulting reaction mixture was heated at about 100° C. for about 4 h, cooled to ambient temperature, and partitioned between EtOAc and brine. The organic layer was separated, dried over MgSO4, filtered, and evaporated. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient, 100%/0% to 50%/50%) to afford 1.05 g (51%) of the title compound: LC/MS (Table 1, Method g) Rt=3.45 min; MS m/z: 396.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].CC([O-])(C)C.[K+].C1COCC1.[C:20]([C:24]1[S:28]/[C:27](=[N:29]\[C:30](=[O:42])[C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=2F)/[N:26]([CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([C:24]1[S:28]/[C:27](=[N:29]\[C:30](=[O:42])[C:31]2[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][C:32]=2[O:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)/[N:26]([CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: Cn1ccnc1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1ccnc1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of (1-methyl-1H-imidazol-2-yl)methanol (109 mg, 0.94 mmol) in THF (5 mL) was treated with a 1 M KOtBu/THF (0.95 mL, 0.944 mmol) and stirred for 15 min. A solution of Example 1A (190 mg, 0.47 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo and partitioned between EtOAc and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by using an Analogix® Intelliflash280™ (SiO2, 0-60% ethyl acetate in hexanes) to afford the title compound (120 mg, 33% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (s, 9 H), 1.50-1.66 (m, 1 H), 1.68-1.96 (m, 3 H), 3.55-3.84 (m, 5 H), 4.05-4.32 (m, 3 H), 5.29 (s, 2 H), 6.86 (s, 1 H), 7.20 (s, 1 H), 7.26 (s, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.79 (dd, J=9.0, 2.2 Hz, 1 H), 8.01 (d, J=2.4 Hz, 1 H). MS (DCI/NH3) m/z 523 (M+H)+. Anal. calcd for C25H29F3N4O3S: C, 57.46; H, 5.59; N, 10.72. Found: C, 56.96; H, 5.57; N, 10.46.