Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:4]=1[CH:5]=[O:6].F[B-](F)(F)F.[O:23]=[N+:24]=[O:25].O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:10]([N+:24]([O-:25])=[O:23])=[CH:9][C:8]([C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=[N+]=O
Reactant: COc1ccc(C2(C)CCOCC2)cc1C=O
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C=O)cc(C2(C)CCOCC2)cc1[N+](=O)[O-]
Temperature: -40 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of the crude product containing 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzaldehyde (0.719 g) in ethyl acetate (10.0 mL) was cooled to −40° C., and nitronium tetrafluoroborate (0.597 g, 4.49 mmol) was added thereto. The resulting mixture was stirred for 2 hours while raising the temperature to −10° C. Water was added to the reaction solution and the resulting solution was diluted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10-30/70) to obtain 0.644 g of the captioned compound (92% yield in 2 steps).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[C:20]#[N:21].O>CS(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:18]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=2[C:20]#[N:21])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Oc2ccccc2)cc1
Temperature: 75 °C
Yield: 87.2 %

Procedure:
To a solution of 5.71 g (0.0307 moles) of 4-phenoxyphenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 75° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 4 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried. The crude product was dissolved in CH2CL2 and washed with 10% aqueous NaOH, water and dried (Na2SO4). Removal of solvent in vacuo afforded 8.0 g (87% yield) of product. Recrystallization from ethanol gave purified 2-(4-phenoxyphenoxy)-5-nitrobenzonitrile, mp 150°-151.5° C.
Reaction SMILES: N[C:2]1[C:7]([NH2:8])=[C:6]([OH:9])[N:5]=[CH:4][N:3]=1.[C:10](=O)([O-])O.[Na+].[CH2:15]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30])[CH:16]([CH3:18])[CH3:17].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.Cl>O.C(OCC)(=O)C>[NH2:3][C:2]1[C:7]([NH:8][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:21]([N+:29]([O-:31])=[O:30])[CH:22]=2)=[C:6]([OH:9])[N:5]=[CH:4][CH:10]=1
Reactant: CC(C)COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Reactant: Nc1ncnc(O)c1N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(C(=O)Nc2c(N)ccnc2O)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 66.5 %

Procedure:
4,5-Diamino-6-hydroxypyrimidine (527 mg, 4.18 mmol) was added to an aqueous suspension of sodium hydrogen carbonate (3.15 g, 41.8 mmol) in water (10 mL) under cooling with ice. Subsequently, a solution of 4-isobutoxy-3-nitrobenzoyl chloride (1.08 g, 4.18 mmol) in ethyl acetate (10 mL) was added. The resulting mixture was stirred for 3 hours under cooling with ice, made acetic by addition of 6 M hydrochloric acid, placed under reduced pressure at room temperature to distill ethyl acetate off, and stirred for 30 min. at room temperature. The precipitated solid product was collected by filtration, washed successively with water and diethyl ether, and dried successively in air and reduced pressure, to give 963 mg (yield 69%) of the desired compound in the form of a powdery product.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(Cl)(=O)C>CO>[ClH:34].[NH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: CO
Solvent: CC(=O)Cl
Product: Cl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 221.7 %

Procedure:
In a round-bottomed flask, (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclopentyl)-carbamic acid tert-butyl ester (150 mg, 0.23 mmol) was suspended in methanol (2 ml). The reaction mixture was cooled to 0° C. and acetyl chloride (0.33 ml, 4.64 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated at room temperature and the residue was dried under high vacuum to afford 147 mg (98%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide hydrochloride as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:20][CH:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:5]2[CH:6]=[N:7][C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)=[O:17])[CH3:21]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1

Procedure:
1-Methylethyl-4-{[(6-{4-[(ethyloxy)carbonyl]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate was prepared as an off-white solid from 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 0.13 g, 0.67 mmol), {4-[(ethyloxy)carbonyl]phenyl}boronic acid (0.30 g, 0.84 mmol), 2M Na2CO3 (10 mL) and Pd(PPh3)4 (0.01 g, 0.01 mmol) in DME (10 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.11 (d, 2H, J=8.6 Hz), 7.98 (d, 2H, J=8.6 Hz), 7.72 (d, 1H, J=8.8 Hz), 7.31-7.26 (m, 1H), 4.94-4.87 (m, 1H), 4.38 (q, 2H, J=7.1 Hz), 4.28-4.16 (m, 2H), 3.89 (d, 2H, J=6.4 Hz), 2.82-2.72 (m, 2H), 2.06-1.94 (m, 1H), 1.87-1.80 (m, 4H), 1.39 (t, 3H, J=7.1 Hz), 1.23 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 427 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9 mmol) was reacted with phenyl isocyanate to provide 123 mg of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a light brown solid, m.p. 171.5–172.5° C. Analysis: Calculated for C22H24N6O.0.60 H2O: % C 66.18; % H, 6.36; % N, 21.05; Found: % C, 66.05; % H, 6.43; % N, 20.61.
Reaction SMILES: C(N(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26]C3CCCOC3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)CCC.Cl.[O:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:39]([O:38][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH2:23][CH2:24][CH2:25][OH:26])(=[O:21])=[O:22])=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)[CH2:40][CH2:41][CH2:42][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:9][CH2:8][CH2:7][CH2:6][CH2:11][CH3:10]
Reactant: C1CCOC1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(S(=O)(=O)CCCOC3CCCOC3)cc2)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C=Cc2ccc(S(=O)(=O)CCCO)cc2)cc1
Temperature: 50 °C

Procedure:
9.02 g (13.8 mmol) of 3i are dissolved in 140 ml of tetrahydrofuran. After addition of 100 ml of 2M hydrochloric acid the mixture is heated at 50° C. for 4 hours. The mixture becomes turbid and on cooling a colorless precipitate separates, which is filtered off and first washed with a little THF and then with water. The solid is dried in a vacuum desiccator. 4.50 g of colorless powder of m.p. 137° C. are obtained. The mother liquor is concentrated, extracted a number of times with dichloromethane, the extracts are dried with magnesium sulfate, the solvent distilled off and the resulting oily residue is chromatographed with isohexane/acetic ester mixtures on a silica gel column. A total of 5.90 g (75%) of product are isolated.
Reaction SMILES: N1C2C(=CC(N[N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])=CC=2)C=CC=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.C(#N)CC#N.O.[NH2:35][NH2:36]>>[N:25]1[C:26]2[C:21](=[CH:20][C:19]([NH:18][N:12]=[C:13]3[C:14]([NH2:15])=[N:36][N:35]=[C:16]3[NH2:17])=[CH:28][CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc2ncccc2c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc2ncccc2c1
Yield: 20 %

Procedure:
4-(Quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 2-(quinolin-6-ylhydrazono)malononitrile (0.11 g, 0.5 mmol) which was derived from 6-aminoquinoline (0.144 g, 1.0 mmol) and malononitrile (1.5 mmol) in a manner similar to that described in Example 2, and hydrazine hydrate. The resulting solid was isolated by filtration and purified by flash chromatography to yield 0.025 g (20%) of the title compound as an orange solid; 1H NMR (ppm, 200 MHz, DMSO-d6) δ 5.95 (br s, 2H), 6.45 (br s, 2H), 7.40–7.55 (m, 1H), 7.98 (d, 1H), 8.10 (s, 1H), 8.20–8.40 (m, 2H), 8.79 (d, 1H), 10.35 (br s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][OH:8].O[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][O:8][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1
Reactant: OCc1cnccn1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2cnccn2)cc1
Yield: 38.7 %

Procedure:
To a stirred and cooled (≤5° C.) solution of 8.3 parts of 2-pyrazinemethanol, 13.3 parts of ethyl 4-hydroxybenzoate and 20.2 parts of triphenylphosphine in 178 parts of tetrahydrofuran was added dropwise a solution of 13.93 parts of diethyl azodicarboxylate in 45 parts of tetrahydrofuran. Upon completion, the reaction mixture was stirred over weekend. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol, yielding 7.5 parts (38.7%) of ethyl 4-(2-pyrazinylmethoxy)benzoate; mp. 76.1° C. (interm. 9).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][N:8]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:4][C:3]=1[F:13]
Reactant: N#Cc1c[nH]c2cc(Br)c(F)cc12
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1cn(Cc2cccc(F)c2)c2cc(Br)c(F)cc12

Procedure:
The title compound was prepared as described in Example 28A using 6-bromo-5-fluoro-1H-indole-3-carbonitrile in place of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile and using 1-(bromomethyl)-3-fluorobenzene in place of 4-(bromomethyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)#[N:7].C(O[CH2:18][CH3:19])C>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C@H:19]2[CH:18]=[CH:5][C:1]3[C:2](=[CH:5][CH:1]=[CH:2][CH:3]=3)[C@@H:3]2[OH:4])=[CH:10][CH:9]=1)#[N:7]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOCC
Product: N#Cc1ccc(O[C@H]2C=Cc3ccccc3[C@@H]2O)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-cyanophenol (413 mg, 3.47 mmol). The mixture was heated at 80° C. for 5 hours, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) giving a white crystalline solid 4 (160 mg, 88%). The ee was determined to be 97% by HPLC analysis on a CHIRALCEL OD column, λ=256 nm. Retention times in 3% isopropanol in hexanes were 35.3 min and 37.7 min (major). Fr=0.40 on silica (30% ethyl acetate in hexanes); mp 140-141° C. (Et2O); [α]25D=+182.3° (c=11.2, CHCl3) IR (KBr, cm31 1) 3303 (b) 3050 (w) 2210 (m) 1598 (s) 1503 (s) 1238 (s) 1025 (m) 859 (m) 778 (m); 1H NMR (400 MHz, CDCl3): δ7.62-7.57 (3H, m), 7.33-7.27 (3H, m), 7.14-7.12 (1H, m), 6.56 (1H, dd, J=1.4, 9.7 Hz), 5.93 (1H, dd, J=1.4, 9.7 Hz), 5.20-5.13 (2H, m), 2.25 (1H, s). 13C NMR (400 MHz, CDCl3): δ160.8, 135.0, 134.2, 131.5, 130.0, 128.5, 128.3, 126.7, 125.4, 124.4, 119.0, 116.2, 104.6, 79.2, 72.0. HRMS calcd for (M-H2O)+ (C17H11ON): 245.0841. Found: 245.0845.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]=[O:16].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:15](=[O:16])[N:12]([CH2:11][Cl:19])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Reactant: C=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=c1ccc(-c2cccc(Br)c2)nn1CCl

Procedure:
To 50 ml of dry benzene were added 2.51 g of 6-(3-bromophenyl)-3(2H)-pyridazinone, 0.45 g of paraformaldehyde and 1 ml of thionyl chloride, after which the mixture was heated under reflux for 1 hour. The mixture was then cooled and filtered, and the filtrate was evaporated to dryness under reduced pressure, to give 3.11 g of crude crystals of the desired Compound No. 5. These were recrystallised from a 4:1 by volume mixture of hexane and benzene, to give 2.0 g of pure Compound No. 5, in the form of white needles melting at 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16]1([S:22]N2C(=O)CCC2=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.B(F)(F)F.CCOCC>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[C:16]1([S:22][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Sc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1Sc1ccccc1
Reaction time: 2 h

Procedure:
To a partial suspension of ethyl 5-chloroindole-2-carboxylate (698 mg, 3.1 mmol) and N-(phenylthio)succinimide (683 mg, 3.3 mmol) in anhydrous methylene chloride (20 mL) at ambient temperature under an inert gas atmosphere was added boron trifluoride etherate (0.12 mL, 1.0 mmol). The reaction was monitored by tlc (thin layer chromatography) until complete. After 2 hours, the reaction was diluted with chloroform and neutralized with aq. NaHCO3. The organic layer was dried (Na2SO4), filtered through a pad of charcoal, and the solvents evaporated. The residue was triturated with hexanes as the product crystallized out to yield the title product, mp 160°-162° C. [see Table II, mp 163°-164° C⟧ This material was used as is.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:30])[C@@H:7]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:30])[C@@H:7]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OCC(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3c (2.2 g, 1.0 eq) and EtOH (11 mL) at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (304.1 mg, 0.8 equiv) in H2O (4 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed complete as determined by TLC. 1N HCl aqueous solution (32 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (200 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4c. The diastereomeric ratio of crude 4c was determined to be 64/36 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4c (2.20 g, 83% yield) as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop-2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 0.8 g of product m.p. 140-42° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 2.53-2.56 (m, 1H); 4.82 (d, 2H, J=2.2 Hz); 6.20 (s, 1H); 7.02 (d, 1H, J=16 Hz); 7;13 (d, 1H, J−=8.9 Hz); 7.32 (d, 1H, J=16 Hz); 7.35-7.45 (m, 3H); 7.48-7.52 (m, 2H); 7.67 (d, 1H, J=8.9 Hz).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH:10]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:18][C:19]1[C:20]([F:29])=[C:21]2[C:27]([NH2:28])=[CH:26][NH:25][C:22]2=[N:23][CH:24]=1>C1COCC1>[Cl:18][C:19]1[C:20]([F:29])=[C:21]2[C:27]([NH:28][C:15]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:16])=[CH:26][NH:25][C:22]2=[N:23][CH:24]=1
Reactant: Nc1c[nH]c2ncc(Cl)c(F)c12
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1c[nH]c2ncc(Cl)c(F)c12)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (279 mg, 2.16 mmol) followed by cyclopentanecarbonyl chloride (143 mg, 1.08 mmol) were added dropwise to 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 1.08 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then concentrated to dryness. The residue was triturated in water and then filtered. The solid was washed with ACN and dried under vacuum to provide N-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (186 mg, 61% yield) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC(C)(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-2-methyl-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a cream-colored solid: 1H NMR (d6-DMSO) δ 10.35 (1H, s), 8.49 (1H, d, J=1.3 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.6, 5.6 Hz), 7.12 (2H, t, J˜9 Hz), 5.11 (2H, s), 5.09 (1H, m), 4.10 (2H, s), 3.44 (2H, d, J=5 Hz), 3.12 (3H, s), 2.82 (3H, s), 1.32 (6H, s); HRMS calcd for C24H27FN4O5+H+: 471.2044. Found: 471.2040.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=O.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O.C(Cl)Cl>[O:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1/[N:1]=[CH:16]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[C:20]1[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccn1
Reactant: CCCCCC
Reactant: Cc1ccc(O)c(N)c1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)c(/N=C/c2ccccn2)c1
Temperature: -35 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a slurry of 2-amino-4-methylphenol (4.40 g, 35.7 mmol) in 300 mL water, a water solution of pyridine-2-carbaldehyde (3.80 g, 35.5 mmol) was slowly added, forming a yellow slurry. After stirring overnight, the suspension was poured through a frit and the solid washed with water. The orange solid was dissolved in 300 mL CH2Cl2 and extracted with 3×100 mL water, dried over MgSO4 and filtered to give a red solution. The solvent was removed under vacuum to give a red oil. The oil was re-dissolved in CH2Cl2, layered with an equal volume of hexane and cooled to −35° C. to yield yellow crystals of 11(5.56 g, 73% yield).