Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:17](=[O:21])[C:18]([OH:20])=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[N:33]1([CH2:39][CH2:40][O:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]([NH2:52])=[CH:44][CH:43]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([C:17](=[O:21])[C:18]([NH:52][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]([O:41][CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:43][CH:44]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2C(=O)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2C(=O)C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To the crude (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-oxo-acetic acid 34 (0.4 g, 1.4 mmol) in a 40 mL scintillation vial was added oxalyl Chloride (5 mL) and on drop of DMF. The suspension was stirred at rt for 1 h, and concentrated under vacuum. The resulting solid was dissolved in EtOAc (10 mL) and added to 4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (0.45 g, 1.2 mmol) dissolved in EtOAc (10 mL)/50% NaHCO3 (10 mL) and stirred overnight at rt. The mixture was diluted with EtOAc and extracted with NaHCO3. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed affording a dark brown oil. The material was purified by column chromatography (50-100% EtOAc/Hexanes) providing 0.357 g (57%) of the desired compound as a yellow solid. Expected mass=540. Observed mass=541.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:27])[CH2:25][CH2:24][CH2:23][CH:22]1[F:26])#[CH:20]>>[F:26][CH:22]1[CH2:23][CH2:24][CH2:25][C:21]1([C:19]#[C:20][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1)[OH:27]
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Reactant: C#CC1(O)CCCC1F
Product: NC(=O)c1cc2n(n1)-c1cc(C#CC3(O)CCCC3F)ccc1OCC2

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with a 1-ethynyl-2-fluorocyclopentanol to give a mixture of titled compounds after purification by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:30]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=5)=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:37]=1.[NH:38]1CCC(N2C3C=CC=CC=3NC2=O)CC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[N:24]=[CH:25][C:26]([C:27](=[NH:38])[NH2:28])=[CH:29][C:30]=5[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:37]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)c(-c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N=C(N)c1cnc(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (3-1, 0.050 g, 0.103 mmol, prepared according to Scheme 1, but substituting the appropriate amine for (1-4)) in anhydrous THF (3 mL)@0° C. was added LiHMDS (1 M in THF, 0.513 mL, 0.513 mmol). The reaction was allowed to warm to rt and stirred for 1.5 hr. 1M HCl (1.5 mL) was added and reaction stirred for 30 min. 1M NaOH (3 mL) was then added and the resulting mixture was extracted with CH2Cl2 (3×15 mL). The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. Resulting material was triturated with ether and dried in vacuo. HRMS m/z (M+H) Calcd: 505.7571, found: 505.2544.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C[Si](N[Si](C)(C)C)(C)C>[Si:7]([O:4][CH:2]([CH2:1][O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])[CH3:3])([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(O)CO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: 60 °C

Procedure:
1,2-Propanediol (58.8 g, 0.77 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.2 mL trimethylsilyl chloride. A small volume of HMDS (ca. 10 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (170 mL) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50-70° C. Heating was continued at 100° C. (1.5 h), 120° C. (1.0 h), and 140° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 147 g of colorless oil, bp 70-72° C./10 mm. 1H NMR (CDCl3): 3.83 (m, 1 H), 3.50 and 3.38 (AB pattern with additional coupling, 2 H), 1.15 (d, J=7 Hz, 3 H), 0.15 (partially resolved singlets, 18 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH3:16][CH:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:3]=2)[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: ClCc1ccccc1
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 6-hydroxy-α-methyl-2-naphthaleneacetic acid (6.48 g, 30 mmol) in methanol (100 ml) is added sodium methoxide (60 mm). After 10 minutes the solvent is removed and replaced with dimethylformamide (100 ml). Benzyl chloride (7.6 g, 60 mmol) is then added and the reaction mixture is stirred overnight at room temperature. The reaction is then heated at 150° C. for 1 hour. The solvent is then removed and the residue is partitioned between water and methylene chloride. The organic layer is washed with water, dried over magnesium sulfate and evaporated to 11.5 g of crude product. This crude product is extracted with 100 ml hot hexane which affords 3.5 g of white crystals. A final recrystallization from methanol affords 2.5 g of white crystals of the intermediate ethyl ester (21 % yield, m.p. 76°-78° C.).
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=1)[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21]
Reactant: CCOC(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Reactant: C1CCNC1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCCC1

Procedure:
Synthesized as in Example 51 from Intermediate 17 (0.54 g, 1.86 mmol) and pyrollidine (284 mg, 4.0 mmol). This gave 0.415 mg (62%) of product.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][C:38]([CH:42]([O:45][Si](C)(C)C)[C:43]#N)=[C:39]([CH3:41])[N:40]=2)=[CH:32][CH:31]=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH:59](CI)[CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51].Cl>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH:59]([CH2:43][C:42]([C:38]2[S:37][C:36]([C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)=[N:40][C:39]=2[CH3:41])=[O:45])[CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(C#N)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(CI)C1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)CC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
In an argon atmosphere, a solution of 1.8 mol/L lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (1.22 mL, 2.19 mmol), chilled to −78° C., was added to 2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-2-(trimethylsilyloxy)acetonitrile (669 mg, 1.99 mmol) in tetrahydrofuran (2 mL). The mixture was stirred for 20 min, followed by addition of 1-(tert-butoxycarbonyl)-3-iodomethylpiperidine (647 mg, 1.99 mmol) in tetrahydrofuran (2 mL). The mixture was further stirred for 1 hour as it warmed from −78° C. to room temperature. 0.5 mol/L ice-chilled hydrochloric acid was then added and the mixture was further stirred for 10 min. Subsequently, the mixture was extracted with ethyl acetate and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The washed product was dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 429 mg (50%) of the desired compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[O:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:20][CH2:21]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Yield: 59.9 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (10 g) and 4-morpholinopiperidine (27 g), the title compound (9.4 g) was obtained. melting point: 84-86° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:18][CH:17]([NH:19]C(=O)C(F)(F)F)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([O:30]CC)=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:16][CH:17]([NH2:19])[CH2:18]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(NC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 94.9 %

Procedure:
A mixture of 1 g (3.2 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate, 0.98 g (4.8 mmoles) of 3-trifluoroacetamidoazetidine hydrochloride and 2 ml of triethylamine is heated in 15 ml of dimethyl sulphoxide for 4 hours at 80°-5° C. It is diluted with water and extracted with chloroform. The organic phase is washed with water and evaporated yielding 0.31 g (22% of ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-trifluoroacetamido-1-azetidinyl)-4-oxo-3-quinolinecarboxylate which is then hydrolysed by heating a mixture of 0.1 g (0.22 mmoles) of this ester with 5 ml of 1N sodium hydroxide and 5 ml of ethanol. The mixture is cooled, evaporated and acidified with acetic acid. Filtering and washing with water yields 70 mg (96%) of 1-cyclopropyl-6,8-difluoro-7-(3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 214°-6° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of tert-butyl 9-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 0.88 mmol) in DCM (20 mL) was added a solution of HCl in EtOAc (20 mL, 80 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (50 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (a solution of NH3 in MeOH (7 M)/MeOH/DCM (v/v/v)=1/20/60) to give the title compound as a beige solid (100.2 mg, 32%).
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22].CN(C=O)C>O>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([NH:23][C:24]([NH:16][C:13]1[CH:12]=[N:11][C:10]([S:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])=[CH:15][CH:14]=1)=[O:25])=[O:22]
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Reactant: Nc1ccc(S(=O)(=O)C2CCCCC2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1ccc(S(=O)(=O)C2CCCCC2)nc1

Procedure:
2-Cyclohexylsulfonyl-5-aminopyridine (1.0 gram) and 2,6-dimethoxybenzoyl isocyanate (0.9 gram) were mixed in 50 ml. of DMF and stirred at room temperature overnight (about 18 hours). The reaction mixture was then poured into water and filtered to separate the product. It was crystallized from ethyl acetate-hexanes, yield 0.5 gram, m.p., 123°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:5]([N+:15]([O-])=O)[CH:4]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:5]([NH2:15])[CH:4]=1
Reactant: COc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N2CCCCC2)c(N)c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a solution of 1-(4-methoxy-2-nitrophenyl)piperidine (238 mg, 1.01 mmol) in anhydrous ethanol (20 ml) was slowly added anhydrous tin chloride (772 mg, 4.07 mmol) at room temperature. The mixture was refluxed for 1 h. The mixture was cooled to room temperature and then rotary evaporated to get an oily liquid. The liquid was basified with aqueous 2N NaOH (20 ml) to a final pH of 10. The resulting precipitate was filtered and washed with water. The aqueous solution was extracted with ethyl acetate (75 ml), washed with water (2×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to give a dark brown liquid (153 mg, 74%). 1H NMR (CDCl3): 6.90 (d, J=8.7 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.26 (dd, J=2.7, 8.1 Hz, 1H), 4.04 (bs, 2H), 3.69 (s, 3H), 2.75 (s, 4H), 1.70-1.63 (m, 4H), 1.54 (s, 2H).
Reaction SMILES: C[N:2]([CH:4]=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14].[Cl-].[NH4+].N>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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].O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]#[N:2])=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: N
Solvent: O
Product: Cc1cc(F)ccc1C#N
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Into 20 ml of DMF was dissolved 10 g of 1-bromo-4-fluoro-2-methylbenzene, and then 0.2 ml of water was added. Then, 3.72 g of zinc cyanide, 484 mg of 1,1′-bis(diphenylphosphino)ferrocene, and 484 mg of tris(dibenzylideneacetone)dipalladium were added thereto under an argon stream, followed by 2 hours of stirring at 140° C. The reaction solution was ice-cooled, ammonium chloride, aqueous ammonia, and water were added thereto, and the resulting solid was collected by filtration. Then, the solid was washed with methanol and the washing liquid was concentrated to obtain 5.7 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[NH2:25][C@H:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:25][C@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:6]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and (R)-(−)-1-amino indan.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](O)=[O:8].[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([NH2:41])[CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([NH:41][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[C:24]5[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:22][CH:23]=5)[N:18]=[CH:17][CH:16]=4)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH:35]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: Cc1oc2cc(Oc3ccnc4cc(OCCN5CCCC5)ccc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NC(=O)c2c(C)oc3cc(Oc4ccnc5cc(OCCN6CCCC6)ccc45)ccc23)c1
Reaction time: 48 h

Procedure:
A solution of 121-G (43 mg), 4,6-dimethylpyridin-2-amine (25 mg), HATU (132 mg) and Et3N (47 mg) in DMF (2 ml) was heated to 70° C. for 4 hours. A small amount of product was seen by TLC. The reaction was allowed to stay for another 48 hours at room temperature. The reaction mixture was purified by HPLC (20-60% CH3CN/H2O, 0.1% AcOH over 30 min.) to give N-(4,6-dimethylpyridin-2-yl)-2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 121.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)[N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: O=C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(N3CCNC(=O)C3)ncc1OCC2

Procedure:
A solution of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (80.0 mg, 0.242 mmol), piperazin-2-one (48.4 mg, 0.484 mmol), XPhos (23.0 mg, 0.0484 mmol), and Sodium-tert-butoxide (46.5 mg, 0.484 mmol) in was heated in microwave at 125 C for 30 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated to give 307, analyzed by rHPLC. MS: (ESI+)=395.2. 1H NMR (500 MHz, DMSO) δ 8.06 (s, 1H), 8.03 (d, J=5.7 Hz, 2H), 7.93 (s, 1H), 7.59 (s, 1H), 5.72 (dt, J=13.1, 6.6 Hz, 1H), 4.62-4.52 (m, 2H), 4.51-4.39 (m, 2H), 3.94 (s, 2H), 3.73-3.62 (m, 2H), 3.37-3.30 (m, 2H), 1.51 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 86.8 %

Procedure:
To a stirring solution of 4-amino-benzoic acid methyl ester (0.594 g, 3.93 mmol) in a mixture of dichloromethane (15 mL)/pyridine (15 mL) is added 4-methanesulfonyl benzenesulfonyl chloride (1.0 g, 3.93 mmol) and the mixture is allowed to react for 6 h at ambient temperature. The reaction is diluted with ethyl acetate and washed with 1N HCl. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated to give 1.26 g (87%) of the title compound. MS (ES−) (m/e) 368.0 (M−1)−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][C:35]=1[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)=O>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[NH:41])[NH2:42])=[CH:36][C:35]=2[C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 1.79 g of 4-acetylaminobenzoic acid in 50 ml of dried pyridine, was added 3.1 g of DCC. The mixture was stirred for 30 minutes while being cooled in ice. After addition of 3.36 g of 4-amidino-2-benzoylphenol methanesulfonate, the mixture was further stirred overnight. The reaction mixture was removed of the insolubles and mixed with ethyl ether to obtain a colorless solid substance which on recrystallization from methanol yielded 0.9 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-acetylaminobenzoate methanesulfonate.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH2:39][C@@H:40]([CH2:43][CH3:44])[CH2:41][OH:42].CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:39][C@@H:40]([CH2:43][CH3:44])[CH2:41][OH:42])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CC[C@H](N)CO
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CC[C@@H](CO)Nc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (S)-2-aminobutan-1-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (S)-2-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ylamino]-butan-1-ol. MS: (ES+) 461.