Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12](Br)=[CH:11]2)(=O)=O)C=CC=CC=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:26]1([C:12]2[C:13]3[C:18]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(N3CCCCC3)ncnc21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2c[nH]c3ncnc(N4CCCCC4)c23)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
To a stirred solution of the product from Method V (100 mg/0.237 mmol) in 1.0 mL of dioxane was added 32 mg (0.261 mmol) of phenylboronic acid and 75 mg (0.356 mmol) of tribasic potassium phosphate followed by 7 mg (0.006 mmol) of tetrakis(triphenylphosphine) palladium. The resulting mixture was degassed with nitrogen and stirred at 100° C. for 48 h. After cooling to room temperature, 1.0 mL of methanol was added followed by 50 mg of NaOH and the new mixture stirred at room temperature for 1 h. The resulting mixture was then partitioned between dichloromethane and water, the dichloromethane layer dried over MgSO4 and concentrated to dryness in vacuo. The crude product was purified by silica-gel chromatography (2:1 ethyl acetate/hexanes) affording 13 mg (20%) of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 1.33-1.34 (m, 4H), 1.43-1.44 (m, 2H), 3.26-3.28 (m, 4H), 7.12 (s, 1H), 7.27 (t, 1H, J=7.2 Hz), 7.38 (t, 2H, J=8.0 Hz), 7.45 (d, 2H, J=0.8 Hz), 8.42 (s, 1H). LRMS: 279.2 (M+1).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][N:24]1[C:28](=O)[CH2:27][CH2:26][C@H:25]1[CH2:30][C:31]#[N:32]>C1C=CC=CC=1>[CH3:23][N:24]1[C:28](=[S:10])[CH2:27][CH2:26][C@H:25]1[CH2:30][C:31]#[N:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1C(=O)CC[C@H]1CC#N
Solvent: c1ccccc1
Product: CN1C(=S)CC[C@H]1CC#N
Yield: 160.6 %

Procedure:
Lawesson's reagent (Tokyo Kasei Kogyo) (1.54 g, 3.8 mmols) was added to a benzene (25 ml) solution of the 2-((2S)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile (1.05 g, 7.6 mmols), and the mixture was heated for 2 hours under reflux. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 60 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2S)-1-methyl-5-thioxopyrrolidin-2-yl)ethanenitrile (941 mg, 80.6%): IR νmax (film) cm−1: 2246. 1H-NMR (CDCl3)δ: 4.20-4.10 (1H, m), 3.30 (3H, s), 3.25-2.98 (2H, m), 277 (1H, dd, J=17.0, 4.9 Hz), 2.68 (1H, dd, J=17.0, 6.6 Hz), 2.50-2.36 (1H, m), 2.06-1.94 (1H, m). MS m/z: 154 (M+), 114 (100%). HRMS: Calcd. for C7H10N2S: 154.0565 (M+). Found: 154.0561 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][SH:13].Cl>CO>[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][S:13][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCBr
Reactant: FC(F)(F)CCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 50 °C
Yield: 87.7 %

Procedure:
A 100 mL, 3-neck round bottom flask was charged with 3-bromopropanoic acid (500 mg, 3.27 mmol) and methanol (10 mL), potassium hydroxide (KOH, 403 mg, 7.19 mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol (468 mg, 3.60 mmol). The mixture was heated at 50° C. for 4 hours, after which it was acidified with 2 N hydrochloric acid and extracted with methyl tert-butylether (MTBE, 2×10 mL). The organic layer was concentrated to dryness to afford a light yellow oil (580 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.78-2.64 (m, 4H), 2.48-2.32 (m, 2H).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:11].[OH-].[Na+]>C(O)C>[CH2:1]([NH:7][CH2:8][C:9]([NH2:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNCC#N
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCNCC(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In an Erlenmeyer flask of 250 ml, 1 gr (0.072 mol) of n-hexylaminoacetonitrile, 1.22 gr (0.072 mol) of dehydrated cupric chloride and 100 ml of H2O were added. Ethanol was then added until obtention of a homogenous phase. The pH of the solution was adjusted to 10 by means of 1N NaOH and the reaction mixture was stirred for 4 hours at room temperature,; a purple solid was formed and was filtered, resuspended in ammoniac solution and extracted with dichloromethane. The organic phase was three times washed with water, dried on K2CO3 and evaporated. The residue was recrystallized from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O.CCOCC>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Nc1ccc2ncnc(Cl)c2c1
Reaction time: 2 h

Procedure:
A mixture consisting of 3.25 g of 4-chloro-6-nitroquinazoline, 10.8 g of sodium hydrosulfite, and 0.3 g of the phase transfer catalyst (C8H17)3NCH3+Cl− in 97 mL of tetrahydrofuran and 32 mL of water was stirred rapidly for 2 hours. The mixture was diluted with ether and the organic layer was separated. The organic solution was washed with brine and then dried over magnesium sulfate. The solution was passed through a small column of silica gel. The solvent was removed at 30° C. at reduced pressure giving 6-amino-4-chloroquinazoline which is used in the next step without additional purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][C:2]=1[OH:8].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:3][C:2]1=[O:8]
Reactant: Oc1ccnc(O)c1
Reactant: Fc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: O=c1cc(OCc2cccc(F)c2)ccn1Cc1cccc(F)c1
Yield: 37.7 %

Procedure:
According to Scheme 13 Step 1: The title compound was prepared from pyridine-2,4-diol (1 eq, 2.52 mmol, 0.28 g) and 1-(bromomethyl)-3-fluorobenzene (3 eq, 7.56 mmol, 0.93 mL) according to the procedure described for Example 1 Step 2. Reaction conditions: 17 h under reflux in DMF. The crude product was purified by flash chromatography on silica gel (CH2Cl2/AcOEt 90/10) to afford 1-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)pyridin-2(1H)-one as a white solid (0.95 mmol, 0.29 g, 36%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[C:35]#[CH:36])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[F:44][C:45]([F:53])([F:52])[C:46]([C:48]([F:51])([F:50])[F:49])=[O:47]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[C:35]#[C:36][C:46]([C:48]([F:51])([F:50])[F:49])([OH:47])[C:45]([F:53])([F:52])[F:44])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C#C/C=C(\CC)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Product: CC/C(=C\C#CC(O)(C(F)(F)F)C(F)(F)F)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner analogous to example 21, by reaction of 5 g (9.1 mmol) of (E)-1-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)-1-ethyl-but-1-en-3-yne with 4 ml (10 mmol) of a 2.5 M solution of butyllithium and a flow of hexafluoroacetone. The desired product is obtained in the form of a yellow oil (m=3.7 g; Y=57%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([OH:14])=O)=[CH:2]1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NOCC>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([NH:40][CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[O:36][CH3:35])=[O:14])=[CH:2]1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CN
Agent: CCON=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid (179.8 g, 0.403 mol), 2-methoxybenzylamine (56.0 ml, 0.429 mol), and hydroxybenzotriazole hydrate (57.97 g, 0.429 mol) in anhydrous tetrahydrofuran (1.7 L) and anhydrous N,N-dimethylformamide (500 ml) under a nitrogen atmosphere at 0° C., were added triethylamine (60.0 ml, 0.430 mol) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (82.25 g, 0.429 mol). The mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least 20 hours. The mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2×), saturated sodium bicarbonate solution (2×), and brine (2×) was performed. The organic layer-was dried over anhydrous sodium sulfate and concentrated to dryness on a rotary evaporator. The desired product was then recrystallized from hot ethyl acetate to yield 215.8 g (0.381 mol, 95%) of analytically pure material.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[N:17]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCCCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 3 h
Yield: 56 %

Procedure:
tert-Butyl [[[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate (0.30 g, 0.62 mmol) was dissolved in ethyl acetate (15 ml), and a solution of 4 N hydrochloric acid in ethyl acetate (2.0 ml, 8.0 mmol) was added thereto under ice cooling condition. The reaction mixture was stirred at the same temperature for 3 hrs. The precipitated crystals were collected by filtration and recrystallized from methanol-diethyl ether to give the titled compound (0.15 g, 56%)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[OH-].[Na+].C(=O)([O-])[O-:33].[K+].[K+]>O1CCOCC1>[OH:33][C:2]1[C:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCNCC1

Procedure:
A solution of 871 mg of 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline and 2.5 ml of 6 N hydrochloric acid in 8 ml of 1,4-dioxane was refluxed for 3 hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and added with potassium carbonate, and then extracted with 1,2-dichloroethane. The extract was dried, and the solvent was evaporated. The resulting residue was washed with ethyl acetate to give 522 mg of pale brown crystals. Recrystallization from methanol gave pale brown crystals having the melting point of from 242.5 to 244° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:38](Br)[C:39]#[CH:40].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:40][C:39]#[CH:38])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: C#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (23 mg, 0.05 mmol) in dry DMF (1 mL) was added sodium hydride (3 mg, 0.05 mmol) at 0° C. under nitrogen. After 1 h at 0° C., propargyl bromide (16 μL, 0.15 mmol) was added and the resulting mixture was stirred for an additional 1 h at 0° C. A saturated solution of NH4Cl was added and the mixture was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 30% EtOAc in cyclohexane) to give the title compound (17 mg, 68%). 1H NMR (500 MHz, CDCl3): 7.50 (1H, s), 7.31-7.24 (7H, m), 7.22-7.20 (2H,m), 5.01 (1H, br s), 4.92 (2H, s), 4.73 (2H, d), 2.55-2.25 (4H, m), 2.32 (1H, t), 2.09-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=O)[C:20](=[O:23])[C:19]=2[O:24]CC)=[CH:4][CH:3]=1.[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH2:12][CH3:13])[O:14][CH3:15])(=[O:9])=[O:10])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:19](=[O:24])[C:20](=[O:23])[C:21]=2[NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCC(N)CC
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) (100 mg, 0.25 mmol) in THF (2 ml) was added 3-aminopentane (29 mg, 0.25 mmol) The reaction mixture was heated at 50° C. overnight. Further 3-aminopentane (29 mg, 0.25 mmol) was added and the reaction was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 10% citric acid (aq), brine, dried (sodium sulfate) and concentrated in vacuo to give a solid; [M+H]+ 446.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.2 (3H, t, CH3), 1.5 (2H, m), 1.6 (2H, m), 3.3 (2H, m), 3.7 (3H, s, CH3), 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.2 (1H, s).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)C(F)(F)COc1ccc(CCl)cn1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)n1ncc(SCc2ccc(OCC(F)(F)C(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
In 40 ml of acetonitrile were dissolved 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.7 g of 5-chloromethyl-2-(2,2,3,3-tetrafluoropropyloxy)-pyridine, and thereto was added 1.5 g of potassium carbonate. The reaction mixture was stirred overnight at room temperature, poured into water and extracted with benzene. The organic layer was washed with a 5% aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure and the resulting crystals were washed with n-hexane to obtain 4.0 g of 2-t-butyl-4-chloro-5-[{6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridyl}-methylthio]-3(2H)-pyridazinone, m.p. 113.0°~114.0° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])(=[O:3])[CH3:2].[I:27]I.C(OCC)(=O)C.S(=O)(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:24]=[C:23]([I:27])[C:22](=[O:25])[NH:21][C:20]1=[O:26])(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C

Procedure:
454 mg (1.23 mmol) of the above product 4 as starting material, 420 mg (1.66 mmol, 1.3 eq) of iodine and 700 mg (1.27 mmol, 1 eq) of ceric ammonium nitrate are dissolved in 15 mL of anhydrous acetonitrile and heated to 80° C. After the starting material disappears, 100 mL of ethyl acetate and 30 mL (5%) of sodium bisulfate are added in turns. 30 mL of saturated saline is used to wash. After collection and combination with an organic phase, the solution is concentrated by reduced pressure. After purified by rapid column chromatography (acetone/n-hexane=2:3), a white powder product (1-(2′,3′,5′-Tri-O-acetyl-β-D-arabinofuranosyl)-5-iodopyrimidin-2,4(3H)-dione) 5 is obtained. Its weight and yield are 425 mg and 70% respectively.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[C:8]([Br:10])[S:9][C:4]=2[CH:3]=1.[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]>>[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[S:6][C:5]4[CH:7]=[C:8]([Br:10])[S:9][C:4]=4[CH:3]=3)=[CH:35][CH:36]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: Brc1cc2sc(Br)cc2s1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(Br)cc4s3)cc2)[nH]1)C(C)C

Procedure:
Compound 62 was prepared from 2,5-dibromothieno[3,2-b]thiophene (1.678 mmol) and compound 8 (0.383 mmol), following the procedure as described for compound A1, to give compound 62 as a yellow solid in 15% yield. MS (ESI, EI+) m/z=587-589 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=2)[N:7]=1)[CH:9]1[CH2:25][CH2:24][C:12]2([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a suspension of tert-butyl 8-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.30 g, 0.79 mmol) in n-BuOH (4.0 mL) were added 1-methyl-1H-pyrazol-4-amine hydrochloride (0.21 g, 1.58 mmol) and DIPEA (0.41 g, 3.15 mmol). The mixture was stirred in a sealed tube at 150° C. overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a yellow solid (0.22 g, 63%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]3)[N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:15][N:16]3[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]3)[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cccc(Cn3cc([N+](=O)[O-])cn3)n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cccc(Cn3cc(N)cn3)n2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a 0.1M solution of 2-(2-methyl-[1,3]dioxolan-2-yl)-6-(4-nitro-pyrazol-1-ylmethyl)-pyridine (145 mg, 0.50 mmol), iron powder (84 mg, 1.50 mmol) and NH4Cl (135 mg, 2.50 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1N NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. LC-MS-conditions 02: tR=0.56 min; [M+H]+=261.61.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[CH2:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1)[CH3:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][CH3:18])=[CH:24][N:23]=1)[CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Reactant: CCc1ccc(CCl)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(COc2ccc3cc([N+](=O)[O-])cnc3c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
In DMF (9 mL) was dissolved 3-nitro-7-hydroxyquinoline (1.0 g, 5.28 mmol.). Sodium hydride (210 mg, 5.28 mmol.) and 5-ethyl-2-(chloromethyl)pyridine (818 mg, 5.28 mmol.) were added to the resulting solution under chilling with ice. The mixture was stirred overnight at room temperature. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1), to give 710 mg of the desired compound as a yellowish white crystalline product (yield 44%).