Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:29]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:29]=1[S:36][C:10]1[C:11](=[O:13])[O:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:8][C:9]=1[OH:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)c(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example NN; 210 mg, 0.664 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 256 mg, 0.730 mmol), K2CO3 (367 mg, 2.655 mmol), and DMF (4 mL). The reaction was stirred at room temperature overnight and then worked up in the usual fashion. The crude product was flash chromatographed using CH2Cl2 :MeOH (98:2) to give the desired product as a solid, m.p. 100-103° C. 1H NMR (DMSO-6) δ 1.0-2.1 (m, 13 H), 1.45 (s, 9 H), 1.80 (s, 3 H), 2.5-2.6 (2 H +DMSO), 2.7 (d, 1 H), 2.9 (d, 1 H), 6.6-6.7 (d, s, 3 H), 6.77 (s, 1 H), 6.9 (d, 2 H), 9.01 (s, 1 H), 9.13 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[CH:14]\I)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:16])[CH:13]=[CH:14][C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:10]
Reactant: C#Cc1cccnc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1cccnc1

Procedure:
The modified procedure was used to convert 3-Ethynyl-pyridine and (Z)-ethyl-3-iodoacrylate to the title product in 12 hours. Purification by flash chromatography (30% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (200 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.57-8.55 (dd, J=4.9, 1.5, 1H), 7.82-7.79 (td, J=7.8, 1.8, 1H), 7.29-7.26 (m, 1H), 6.38-6.35 (d, J=11.4, 1H), 6.21-6.18 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 1.34-1.31 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.32, 152.25, 149.13, 138.58, 129.22, 122.86, 121.80, 119.68, 96.97, 89.03, 60.34, 14.08. Anal. Calcd. for C12H11NO2: C, 71.63; H, 5.51; N, 6.96; Found C, 71.77; H, 5.64; N, 6.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[N:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[C:23]3[NH2:28])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[N:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[C:23]3[NH:28][C:29](=[O:31])[CH3:30])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 37 mg (0.10 mmol) 5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine in 0.5 ml acetic acid was treated with 20.4 mg (0.20 mmol) acetic acid anhydride and heated to 80° C. The reaction mixture was stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature and partitioned between 25% aqueous ammonia and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was triturated with tert-butyl-methylether yielding N-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-yl}-acetamide as brown crystals; HPLC/MS (A) 1.64 min, [M+H] 410.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([F:24])[CH:18]=4)=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:25])=[CH:4][N:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH:30]=[CH:29][N:28]=[N:27]1>C(O)CCC.O1CCOCC1.O1CCOCC1.CN1C(=O)CCC1.CN1C(=O)CCC1.C(Cl)(Cl)Cl.C(O)(C)C>[N:26]1([CH2:31][CH2:32][NH:33][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]4[C:13]([C:17]5[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([F:24])[CH:18]=5)=[CH:14][CH:15]=[CH:16][C:10]=4[CH:9]=3)[C:5]([F:25])=[CH:4][N:3]=2)[CH:30]=[CH:29][N:28]=[N:27]1
Reactant: NCCn1ccnn1
Reactant: Cc1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCCCO
Product: Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 135 °C
Yield: 57.7 %

Procedure:
Combine 2-chloro-5-fluoro-4-[7-(2-fluoro-5-methyl-pyridin-4-yl)-benzo[b]thiophen-2-yl]-pyrimidine (200 mg, 0.54 mmol) and 2-[1,2,3]triazol-1-yl-ethylamine (120 mg, 21.1 mmol) in n-butanol (2 mL), alternative dioxane, dioxane-NMP (N-methylpyrrolidinone), NMP alone as solvent] in a pressure vessel. Heat the mixture in an oil bath at 120-150° C. overnight (or in microwave reactor for 10-60 min). Dilute the mixture with chloroform/IPA (3/1). Wash the solution with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate the solution in vacuo to a dark residue. Purify by column chromatography (DCM→10% methanol in DCM) to afford the title compound as a yellow solid (140 mg, 59%). MS (ES) m/z 450 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4,5-difluorobenzoic acid (5.37 g, 31.0 mmol) in THF (50 mL) was dropwise added to the suspension on LAH (1.65 g, 43.5 mmol) in THF (15 mL) at room temperature under N2 over 10 min. The resulting suspension was stirred at room temperature for 1 hr. Then the mixture was cooled down to 0° C., quenched with saturated Na2SO4 (100 mL), and extracted with Et2O (2×100 mL), the combined organic layers were washed with brine (60 mL), dried over MgSO4, and concentrated on rotary vacuum to afford the expected crude product as a brown solid, which was pure enough to be used in next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 1 H), 4.56 (s, 2 H), 6.46 (dd, J=11.71, 6.92 Hz, 1 H), 6.87 (dd, J=10.58, 8.56 Hz, 1 H); Mass spec. 160.04 (MH+), Calc. for C7H7F2NO 159.05.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1)([CH3:3])[CH3:2].[I:10]N1C(=O)CCC1=O>C(#N)C>[I:10][C:6]1[NH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][C:7]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c[nH]c(C(C)C)n1
Solvent: CC#N
Product: Cc1nc(C(C)C)[nH]c1I
Yield: 60.9 %

Procedure:
2-Isopropyl-4-methyl-1H-imidazole (3.96 g, 32 mmol) and N-iodosuccinimide (8.33 g, 35 mmol) were dissolved in acetonitrile (100 mL) and heated to reflux for 16 hours. The reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-40% EtOAc in hexane) to give 4.87 g (61%) of the title compound as a yellow solid. m/z (ES+) 251 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1>C(O)C>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Solvent: CCO
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1I
Yield: 94 %

Procedure:
The desired compound was prepared according to the procedure of Example 212, step 4 (racemic mixture), using 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone instead of tert-butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate as the starting material in 94% yield as a 96:4 mixture of enantiomers (RT=3.56 min and 4.28 min; Chiral Technologies ChiralPak AD-H column, 20×250 mm, 5 micron particle size, eluting with 5% ethanol in hexanes at 1 ml/min). LCMS for C11H13ClIO (M-(OH))+: m/z=323.0; Found: 322.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[CH:12]=[CH:13][C:14]([OH:16])=[O:15])#[N:8]>O>[C:7]([C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:17]=[CH:18][CH:19]=1)#[N:8]
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(CCC(=O)O)c1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To 200 ml of a solution of 20.0 g potassium carbonate in 250 ml water, 15 g of 3-cyanocinnamic acid was added; the resulting mixture was heated until all the acid was in solution. The solution was cooled and filtered and rinsed with water to 250 ml total volume. Then 0.95 g of 10% palladium on carbon was added and the solution was hydrogenated at 8.5 psi for two hours. The reaction mixture was filtered, and then acidified to a pH of about 1 by the dropwise addition of concentrated hydrochloric acid, being careful to avoid too much foaming. The mixture was chilled in an ice bath and filtered to collect the precipitated product acid. The precipitate was rinsed several times with cold water and dried overnight, to give 13 g of the above-identified product as a solid, melting point 95° C.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C@H:6]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[N:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:18]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])C.[OH-].[Li+]>C1COCC1.O>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:20]1[N:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:18]=[C:17]([C:15]([NH:14][C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][C:4]([OH:39])=[O:3])=[O:16])[CH:21]=1)#[N:31]
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc(OCc2ccccc2C#N)n(-c2ccccc2F)n1)c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCc2ccccc2C#N)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
210 mg (0.4 mmol) of (S)-3-{[5-(2-cyano-benzyloxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-3-o-tolyl-propionic acid ethyl ester were dissolved in a mixture of THF, MOH and water (2 ml each), lithium hydroxide (28.7 mg, 1.2 mmol) was added, and the mixture was stirred for 3 h at room temperature. After evaporation of the solvent the residue was subjected to aqueous work-up using EA and a 10% aqueous solution of citric acid. After evaporation of the organic phase the residue was subjected to column chromatography (silica gel, DCM/MOH 10:1) to give 45 mg (23%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:41]1[CH2:46][CH2:45][O:44][C:43]2[CH:47]=[C:48]([C@@H:51]([O:55][C:56]3[CH:57]=[C:58]4[C:62](=[CH:63][CH:64]=3)[N:61]([C:65]3[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=3)[N:60]=[CH:59]4)[C@@H:52]([NH2:54])[CH3:53])[CH:49]=[CH:50][C:42]1=2>CN1C(=O)CCC1.O>[O:41]1[CH2:46][CH2:45][O:44][C:43]2[CH:47]=[C:48]([C@@H:51]([O:55][C:56]3[CH:57]=[C:58]4[C:62](=[CH:63][CH:64]=3)[N:61]([C:65]3[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=3)[N:60]=[CH:59]4)[C@@H:52]([NH:54][C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:7])[CH3:53])[CH:49]=[CH:50][C:42]1=2
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](NC(=O)C1(C)CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-methylcyclopropanecarboxylic acid (39 mg, 0.39 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (170 μl, 0.97 mmol) in NMP (2 mL) was stirred at r.t. for 5 min until a solution had formed. To this solution was added (1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (19a) (102 mg, 0.24 mmol) dissolved in NMP (1 mL). The reaction mixture was stirred for 2 h at r.t. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL), the organic phases was then washed with brine, dried over Na2SO4, filtered and evaporated. The remaining oily residue was purified by HPLC. Fractions containing product was freezedried. Yield 68 mg (55%10).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:33]([CH3:35])[CH3:34])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N(C)C)C3)ccc21
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 51, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[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].O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Add (S)-2-sec-butylamino-6-chloroisonicotinic acid methyl ester (1.40 g, 5.75 mmol), 2-fluorophenylboronic acid (1.0 g, 7.15 mmol), tetrakis(triphenylphosphine)palladium (0) (0.664 g, 0.575 mmol), potassium carbonate (2.38 g, 17.3 mmol) and 1,4-dioxane (25 mL) to a sealed flask flushed with nitrogen. Heat and stir the mixture overnight and cool to room temperature. Filter the mixture through a filtering agent, concentrate and purify (silica gel chromatography, eluting with 4:96 ethyl acetate:hexanes) to give the title compound (1.31 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.C([O-])([O-])=O.[K+].[K+].[CH2:17]([Zn]CC)[CH3:18]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH2:17][CH3:18]
Reactant: CC[Zn]CC
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ncc(CO)cc1Cl
Yield: 21.4 %

Procedure:
To a solution of (5,6-dichloro-3-pyridinyl)methanol (500 mg, 2.81 mmol), K2CO3 (1165 mg, 8.43 mmol), and [1,1′-Bis(diphenylphosphino) ferrocene]dichloro-palladium(II) (206 mg, 0.281 mmol) in THF (17 ml), was added diethylzinc (5.67 ml, 5.67 mmol). The mixture was stirred under reflux for 16 h in a pressure tube. The resulting mixture was quenched upon the addition of aqueous HCl until pH 7 and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography using Flashmaster II, spherical silica gel cartridge BP-SUP 20-40μ, and mixtures of EtOAc and hexane as eluents to give 103 mg of desired compound.
Reaction SMILES: O[NH:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].S(Cl)(Cl)=O.C(N(CCCC)CCCC)CCC.[OH-].[Na+]>C(OC)(C)(C)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3]([OH:12])=[N:2][O:11][C:5]=2[CH:6]=1
Reactant: Cc1ccc(C(=O)NO)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Product: Cc1ccc2c(O)noc2c1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
50.0 g of N,2-dihydroxy-4-methylbenzamide was added to 350 mL of tert-butylmethylether, and 38.1 g of thionyl chloride was added dropwise at −1-0° C. This was stirred for 30 minutes at the same temperature. Then, 164 mL of tributylamine was added dropwise at −5-−3° C., and this was stirred for 1.5 hours at −5-5° C. To the reaction mixture, 200 mL of 20% sodium hydroxide aqueous solution was added, an organic layer was separated, and 100 mL of water, 42 mL of 20% sodium hydroxide aqueous solution and 5.0 g of celite were added. After insoluble matter was filtered off, the cake was washed with 100 mL of water. The filtrate and the washing solution were combined and an aqueous layer was separated. To the aqueous layer, 10 mL of acetone and 50 mL of acetic acid were added at 40-50° C. After stirring at the same temperature for 30 minutes, solids were filtered to obtain 40.1 g of 6-methyl-1,2-benzisoxazol-3-ol in the form of a pale yellow solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:17][CH3:18])=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[N:30]1([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:41]/[C:19](=[C:6]3\[C:5](=[O:29])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:16][CH2:17][CH3:18])=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=4)/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OCC)c(OCC)cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: CCOc1cc2c(cc1OCC)/C(=C(/Nc1ccc(CN3CCCCC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C)C=O>O>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCCCCOc1cccc2ccccc12

Procedure:
A mixture of 1-naphthol (12.9 g), potassium carbonate (23.5 g), 1-chloro-8-(p-toluenesulphonyloxy)octane (23.5 g) and dimethylformamide (200 ml) was stirred at 55° for 2-1/2 days. The solution was then cooled and added to water, and extracted with ether. The extract was dried and evaporated and the residue was chromatographed on silica gel (750 g), eluting with 3:1 hexane: methylene chloride, so as to afford the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+].Cl>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2cccc(F)c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2cccc(F)c2)n1)C(=O)O
Temperature: 0 °C

Procedure:
Four g of the product of Example 57 was combined with 1.6 g of potassium hydroxide in 100 ml of ethanol, and the mixture was heated briefly to reflux. It was then cooled poured over ice-water, and made acid with hydrochloric acid. The product was collected by filtration and dried to obtain 3.4 g of the desired compound, m.p. 177°-179°.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(S)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (0° C.), stirred slurry of 1.7 g of sodium hydride oil dispersion (60%) in 100 mL of dry THF, under argon, is added via cannula 4.95 g of 3-aminothiophenol in 5 mL of THF. After 5 min, 4.6 mL of benzyl chloride is added. The mixture is allowed to warm to room temperature and stirred for 18 h, then cooled to 0° C. and partitioned between water and diethyl ether. The organic phase is washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residual oil on silica using 30% ethyl acetate in heptane provides 7.57 g of the title compound as a beige crystalline solid, which may be recrystallized from ether-hexane.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11]O>Cl>[O:1]([CH3:11])[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Product: COC1O[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 95 %

Procedure:
D-Arabinose (1, 25 g, 167 mmol) was stirred for 5 hours in 0.5% hydrogen chloride in methanol (675 mL) at room temperature and then neutralized with Amberlite IRA-400 OH anion exchange resin. The filtrate and washings were combined and evaporated to dryness and the crude product was purified by silica gel chromatography (CHCl3/MeOH, 92:8) to afford 26.2 g of methyl D-arabinofuranoside (2, 95% yield) as an and (1:1) mixture. MS 164 (M)+.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:51])([F:50])[C:41]1[N:42]=[CH:43][C:44]([C:47](O)=[O:48])=[N:45][CH:46]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:11][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:47]([C:44]5[CH:43]=[N:42][C:41]([C:40]([F:50])([F:39])[F:51])=[CH:46][N:45]=5)=[O:48])[CH2:5][CH2:6]4)[CH2:13]3)[CH:15]=2)=[N:24][CH:23]=1
Reactant: O=C(O)c1cnc(C(F)(F)F)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Product: N#CCC1(n2ccc(-c3ncnc4[nH]ccc34)c2)CN(C2CCN(C(=O)c3cnc(C(F)(F)F)cn3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-trifluoromethylpyrazin-2-ylcarboxylic acid following the procedure described for Example 261, followed by purification with HPLC (method B) provided the title compound. LC-MS: 536.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.99 (brs, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.62 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.11 (s, 1H), 6.98 (d, 2H), 4.12 (m 1H), 3.65 (d, 2H), 3.55 (d, 2H), 3.41 (m, 1H), 3.31 (s, 2H), 3.15 (m, 2H), 2.60 (m, 1H), 1.90-1.60 (m, 2H), 1.30 (m, 2H).