Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[C:13]1[N:18]([CH3:19])[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:19][N:18]1[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=[C:13]1[NH:2][CH2:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCC(=O)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(NCC(=O)c2ccccc2)nc(-c2ccncc2)cc1=O
Yield: 57.9 %

Procedure:
A solution of 2-amino-1-phenyl-ethanone hydrochloride (1.03 g, 6.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.665 g, 3.00 mmol), 4-dimethylaminopiridine (36.0 mg, 0.30 mmol) and triethylamine (0.80 ml, 6.00 mmol) in dimethylsulfoxide (15 ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered and washed with refluxing diethyl ether to give the title compound (0.556 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CCOCC>[N:1]([C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
This reaction was performed in a dark environment. To a cold (0–5° C.) solution of 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (46 mg, 0.10 mmol) in acetic acid (3 mL) was added sodium nitrite (0.31 mL of a 25 mg/mL aqueous stock solution, 7.7 mg, 0.11 mmol). The mixture turned dark and was stirred for 20 minutes at 0° C. Sodium azide was then added and the mixture was stirred for 20 minutes, allowed to warm to room temperature and stirred for an additional 10 minutes. Ether was added and the mixture was neutralized with sodium bicarbonate. Aqueous workup was followed by drying over sodium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided 2-(3-azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (25 mg, 52%) as a yellow solid. 1H NMR (CDCl3): δ 8.05 (d, 1 H), 7.75 (d, 1 H), 7.45–7.42 (m, 3 H), 7.36 (t, 1 H), 7.13 (m, 1 H), 6.33 (d, 1 H), 6.10–6.03 (m, 2 H), 5.10 (d, 1 H), 4.36 (m, 1 H), 4.05 (m, 1 H), 2.20–1.54 (m, 16 H); MS m/z 480 (M+1); IR 2109 cm−1.
Reaction SMILES: S(=O)(=O)(O)N.[Cl:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]([C:14]3[N:15]=[C:16]4[C:22]([CH:23]=[O:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:17]4=[N:18][CH:19]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1.Cl([O-])=[O:36].[Na+].P([O-])(O)(O)=O.[K+]>O.CCOC(C)=O.O1CCOCC1>[Cl:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]([C:14]3[N:15]=[C:16]4[C:22]([C:23]([OH:36])=[O:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:17]4=[N:18][CH:19]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-n3cnc4cc(Cl)ccc43)cnc21
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-n3cnc4cc(Cl)ccc43)cnc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
In a 50 mL round-bottomed flask, sulfamic acid (187 mg, 1.54 mmol) and 2-(5-chloro-benzoimidazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (110 mg, 0.26 mmol) were combined with dioxane (6 ml) to give a off-white suspension. The reaction mixture was cooled to 5° C. and a solution of sodium chlorite (30.2 mg, 0.33 mmol) and potassium dihydrogen phosphate (35.0 mg, 0.26 mmol) in water (2 ml) was added dropwise via syringe over 5 min. The reaction warmed to room temperature and stirred for 1 h. The reaction was diluted with EtOAc (25 ml) and washed with 50% brine/water. The aqueous layer was back-extracted with EtOAc (15 mL). The organic layers were combined, washed with brine and dried (MgSO4). Evaporation of the solvent gave 90 mg (79%) of 2-(5-chloro-benzoimidazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a solid. (M+H)+=444.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2Cl)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cccc(Cl)c2Cl)CCNC1
Reaction time: 0.5 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(2,3-dichlorophenyl)-3-hydroxypyrrolidin-1-carboxylate (1.23 g, 3.7 mmol), dichloromethane (20 mL), trifluoroacetic acid (3 mL). Stirred for 0.5 h. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 0:100). Yield: 0.35 g. MS m/z (rel. intensity, 70 eV) 233 (M+, 6), 231 (M+, 10), 198 (32), 196 (bp), 75 (37), 56 (27).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28]([N:30](C(OC(C)(C)C)=O)[C@@H:31]([C:45](O)=O)[CH2:32][CH2:33][C@@H:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=1[F:44])[CH2:35][NH2:36])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[F:44][C:38]1[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=1[C@H:34]1[CH2:35][NH:36][C:45](=[S:10])[C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:32][CH2:33]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (2.90 g, 7.18 mmol) was added to a suspension of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (4.79 g, 14.1 mmol, described in Intermediate 4) in toluene (250 mL) and the mixture was heated to 90° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 85:15.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:36][CH2:35][CH:30]1[N:29]([CH3:28])[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:27]=[CH:26][C:9]3[N:10]=[C:11]([NH:14][CH:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][C:22]=5[O:24][CH3:25])[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31]1
Reactant: CN1CCNCC1CO
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)C(CO)C4)cc3CO1)CC2
Yield: 67 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55, step A) (150 mg, 0.39 mmol), commercially available rac-(1-methyl-piperazin-2-yl)-methanol (CAS no. 141108-61-4) (76 mg, 0.58 mmol) and diisopropylethyl amine (198 ul, 1.17 mmol) in acetonitrile (5 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (125 mg, 67%), MS (ISP) m/e=480.2 [(M+H)+].
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1O)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:18]([OH:22])(=[O:21])[CH:19]=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[C:1]([C:6]1[CH:7]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:9]2[O:22][C:18](=[O:21])[CH:19]([OH:20])[C:10]=2[CH:11]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CCC(C)(C)c1cc2c(c(C(C)(C)CC)c1)OC(=O)C2O
Temperature: 25 °C

Procedure:
2,6-Di-tert-pentylphenol (161.4 g), glyoxylic acid (122.3 g of the 50% b.w. solution in water) and 1.3 g of p-toluene sulphonic acid are heated in 500 ml of ethylenechloride under nitrogen at reflux temperature in an apparatus designed for the removal of water. After 3.5 hours the reaction mixture is cooled to room temperature, washed 3 times with 25 ml water, dried over magnesium sulphite and evaporated under reduced pressure to give 214.3 g of: 5,7-di-tert-pentyl-3-hydroxy-3H-benzofuran-2-one as an orange coloured oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH2:11]([O:13]/[N:14]=[C:15](/[C:44]1[N:48]=[C:47]([NH2:49])[S:46][N:45]=1)\[C:16]([NH:18][C@@H:19]1[C:26](=[O:27])[N:25]2[C@@H:20]1[S:21][CH2:22][C:23]([S:31][C:32]1[S:33][CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][N+:40]([CH3:43])=[CH:39][CH:38]=3)[N:36]=1)=[C:24]2[C:28]([O-:30])=[O:29])=[O:17])[CH3:12].CC(C)=O>CC(N(C)C)=O>[CH2:11]([O:13]/[N:14]=[C:15](/[C:44]1[N:48]=[C:47]([NH:49][C:1](=[O:3])[CH3:2])[S:46][N:45]=1)\[C:16]([NH:18][C@@H:19]1[C:26](=[O:27])[N:25]2[C@@H:20]1[S:21][CH2:22][C:23]([S:31][C:32]1[S:33][CH:34]=[C:35]([C:37]3[CH:38]=[CH:39][N+:40]([CH3:43])=[CH:41][CH:42]=3)[N:36]=1)=[C:24]2[C:28]([O-:30])=[O:29])=[O:17])[CH3:12]
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CS[C@H]12)c1nsc(N)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CS[C@H]12)c1nsc(NC(C)=O)n1
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
Acetyl chloride (129.90 g, 1654.77 mmol) and pyridine (23.47 g, 296.67 mmol) were added to a solution of (6R,7R)-7-[[(2Z)-2-(ethoxyimino)-2-[5-(amino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[[4-(1-methylpyridinium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicylo[4.2.0]oct-2-ene-2-carboxylate (100 g, 164.82 mmol) in dimethylacetamide (1300 ml) and the resulting mixture was stirred at 0-5° C. for 4 to 6 hours. The reaction mixture was then poured into excess acetone to form a slurry which was filtered and dried at room temperature overnight in vacuo to afford 97 g of crude (6R,7R)-7-[[(2Z)-2-(ethoxyimino)-2-[5-(acetamido)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[[4-(1-methylpyridinium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicylo[4.2.0]oct-2-ene-2-carboxylate. 63% purity by HPLC area % assay (Luna 3 micron C18, 3.0 mm×50 mm; NH4OAc/CH3CN; 1.0 ml/min flow rate)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[N:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:3]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)nn1C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Temperature: 100 °C
Yield: 34.7 %

Procedure:
1.50 g (5.36 mmol) of methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (for preparation see WO2007/034278A2), 1.21 g (5.36 mmol) of 1-bromo-4-(trifluoromethyl)benzene and bis(triphenylphosphine)palladium(II) chloride are initially introduced under argon and admixed with 6.69 ml of a 2M solution of sodium carbonate in water and 20 ml of dioxane. The reaction mixture is heated at 100° C. for three hours and, after cooling over Celite and sodium sulphate, is filtered. The filter cake is afterwashed with ethyl acetate and the filtrate is concentrated by evaporation on a rotary evaporator. Chromatographic purification on silica gel gives 529 mg of methyl 1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate (35%) (for preparation also see DD1984/210265).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.Cl.C(O)C>C(O)C>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[N:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccncc32)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCN(CCn2c(=O)ccc3ccncc32)CC1
Reaction time: 2 h
Yield: 136.8 %

Procedure:
To a solution of 2.8 g of tert-butyl (1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 20 mL of ethanol, 60 mL of a 6.2 mol/L hydrogen chloride/ethanol solution was added at room temperature, and the mixture was stirred for 2 hours. Thereto was further added 60 mL of a 6.2 mol/L hydrogen chloride/ethanol solution, and the mixture was stirred for 4 hours and then left for 4 days. The solvent was distilled off under reduced pressure, diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 2.8 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][NH2:14]>C(O)(C)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[NH:14][N:13]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: NN
Solvent: CC(C)O
Product: Nc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 80 °C

Procedure:
To a solution of 2-fluoro-4-nitrobenzonitrile (10 mmol) in isopropanol (30 mL) was added aqueous hydrazine (4 mL). The resulting solution was heated at 80° C. for 12 h. The reaction mixture was then concentrated, water (30 mL) was added, and the solution was extracted with ethyl acetate (2×25 mL). The combined organics were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The volatiles were removed in vacuo yielding 3-amino-6-nitroindazole as an orange solid, which was utilized for further transformation without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][CH2:9][C:10]([CH3:28])=[CH:11][CH2:12][CH2:13][CH:14]=[C:15]([CH3:27])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:3][CH2:4][CH2:5][OH:6].O.[CH:30](OCC)=[CH2:31]>C([O-])(=O)C.C([O-])(=O)C.[Hg+2]>[CH:30]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])=[CH:7][CH2:8][CH2:9][C:10]([CH3:28])=[CH:11][CH2:12][CH:13]=[CH:14][CH:15]([CH3:27])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH2:31]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCCO
Reactant: C=COCC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Product: C=COCCCC(C)=CCCC(C)=CCC=CC(C)CCC=C(C)CCC=C(C)C

Procedure:
Mercury diacetate (0.33 g, 1.03 mmol) was added to a solution of 4,8,13,17,21-pentamethyl-4,8,12,16,20-docosapentaen-1-ol (2.00 g, 5.17 mmol) in 50 ml of ethyl vinyl ether and the reaction refluxed overnight. The reaction was poured into 350 ml of water and extracted with ether. Theether extracts were washed with brine and dried over magnesium sulfate. Removal of the ether in vacuo gave the crude material which was purified by flash chromatography usin9 95/5 (hexane/ethyl acetate), to give 1.69 g of 4,8,13,17,21-pentamethyl-4,8,11,16,20-docosapentaen-1-ol vinyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:12]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][N:26]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C>O1CCCC1.C(O)C.O.NN>[NH2:26][CH2:25][CH2:24][CH2:23][C:22]#[C:21][C:12]1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:10][CH:11]=1
Reactant: COCCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 2-(5-(2-((3-fluorophenyl)amino)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J6, 90 mg) in tetrahydrofuran (1 mL) and ethanol (0.5 mL), hydrazine monohydrate (100 μL) was added at room temperature, and the mixture was stirred for 1 hour under reflux by heating. The reaction mixture was cooled to room temperature, and then ethyl acetate was added to the reaction mixture. The insoluble matter was removed by filtration, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The aqueous layer was separated, 3.0 mol/L aqueous sodium hydroxide was added until the mixture became basic, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 5-(5-amino-1-pentyn-1-yl)-N2-(3-fluorophenyl)-N4-(3-methoxypropyl)pyrimidine-2,4-diamine (J7, 55 mg) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:49])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)[CH3:36]>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>[CH2:35]([O:37][C:38](=[O:49])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)=[CH:44][CH:43]=1)[CH3:36]
Reactant: CCOC(=O)CCCc1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CCCc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, 4-(4-bromo-phenyl)-butyric acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide 4-(4′-{4-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-butyric acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=2)[NH:18][C:17]([C:29]([OH:31])=O)=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.O[N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:21]=2)[NH:18][C:17]([C:29]([NH2:34])=[O:31])=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 5-{[6-(methylsulfonylmethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (4.9 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole monohydrate (2.68 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.3 g), and 25% aqueous ammonia (15 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (3.0 g, yield 58%) as pale-yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([C:20](=[N:22][OH:23])[NH2:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.CO.CCCCCC>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([C:20](=[N:22][OH:23])[NH2:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: NC(=NO)c1ccc(-c2ccc(OCc3ccccc3)cc2)o1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=NO)c1ccc(-c2ccc(O)cc2)o1

Procedure:
A mixture of 15 g (0.048 mole) of the compound of Example V, 1 tsp. of 5% Pd/C, 50% H2O, and 135 ml of methanol was shaken under hydrogen pressure with the theoretical amount of H2 being absorbed. The catalyst was removed by filtration and the solvent removed on the Calab evaporator to give a residual solid. The solid was refluxed in 750 ml of ethyl acetate, cooled in an ice bath and the insoluble material removed by filtration. The filtrate was reduced to 300 ml volume on the Calab evaporator and then diluted with hexane. The resulting solid was filtered and air dried to yield 5.4 g (46%). An analytical sample was prepared by dissolving a sample in refluxing ethyl acetate and adding hexane to the cloud point. This procedure was repeated three times, m.p. 157°-158°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].Cl>CO>[OH:11][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:9][S:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(CSCc1ccncc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(C(O)CSCc2ccncc2)cc1
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, alpha-(4-picolylthio)-p-nitroacetophenone (0.45 g., 1.56 mmoles) and sodium cyanoborohydride (0.10 g., 1.56 mmoles) were dissolved in 15 ml. of dry methanol and a trace of bromocressol green pH indicator added (blue at 5.5, yellow at pH 3.8). The reaction was blue-green in color. Methanolic hydrogen chloride was added dropwise until the reaction turned yellow (pH approximately 4). Small additions of the methanolic hydrogen chloride were made, whenever the reaction darkened, for a period of 4 hours. The reaction was then left to stir for an additional 16 hours. The reaction mixture was concentrated to an oil which was taken up in 10 ml. of water and the product extracted into ethyl acetate (3 times 20 ml.). The combined ethyl acetate was back-washed with saturated sodium bicarbonate (2 times 15 ml.) and then with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to yield 4-[2-hydroxy-2-(4-nitrophenyl)ethylthiomethyl]pyridine [0.347 g.; m.p. 135° -137° C.; ir (KBr): 3.25, 6.25, 6.6, 7.35, 9.35, 11.75, 13.75μ; pnmr/DMSO-d6 /TMS/τ: 7.2 (d, 2H), 6.5 (broad s, 1H). 6.2 (s, 2H), 5.1 (t, 1H), 2.6 (d, 2H), 2.3 (d, 2H), 1.7 (d, 2H), 1.4 (d, 2H)].