Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:10]2[C:11]([I:13])=[CH:12][C:8]([NH2:3])=[N:9]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccc(F)cc2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cc(I)n(-c2ccc(F)cc2)n1
Temperature: 95 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a suspension of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-5-iodo-1H-pyrazole (625 mg) in ethanol/water (2/1, 12.5 ml) were sequentially added hydroxylammonium chloride (2.28 g) and triethylamine (0.46 ml) at room temperature, and the mixture was stirred at 95° C. for 15 hours. This reaction mixture was cooled to room temperature, concentrated under reduced pressure. To the resulting residue was added a 8M aqueous solution of sodium hydroxide, and then the mixture was extracted with ethyl acetate. This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (318 mg).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:10]=[CH:11][C:12]=1[F:13].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:9]3[CH:10]=[CH:11][C:12]([F:13])=[C:7]([F:6])[CH:8]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(F)c(F)c1)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 3 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 15.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17]C(OC(C)(C)C)=O)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=1[Cl:25])[CH:2]=[CH2:3].C(O)=O>>[CH3:16][O:15][C:13](=[O:14])[C@@H:12]([NH2:17])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:25])[CH:7]=1
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1Cl
Solvent: O=CO
Product: C=CCOc1ccc(C[C@H](N)C(=O)OC)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 10 mL round-bottomed flask, (S)-methyl 3-(4-(allyloxy)-3-chlorophenyl)-2-(tert-butoxycarbonylamino)propanoate (90 mg, 243 μmol, Eq: 1.00) was combined with formic acid (1.12 g, 933 μL, 24.3 mmol, Eq: 100) and stirred at RT for 3 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was neutralised with 5% aqueous Na2CO3 and extracted with DCM (3×). The organic layers were combined and dried over Na2SO4 and concentrated in vacuo to yield a colorless oil (68 mg; 100%). m/z=270.3 [M+H]+; 292.1 [M+Na]+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].CC(O)=O>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=2)=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18]
Reactant: Oc1ccc(I)cc1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)cnc1Oc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 3-neck 12 L flask equipped with an overhead stirrer, thermometer, condenser and nitrogen inlet was charged with NaH (186.1 g, 4.653 mol) and DMF (1500 mL). The slurry was cooled to 0° C. and a solution of 4-iodophenol (488.6 g, 2.221 mol) in DMF (1500 mL) and added. The temperature of the reaction mixture was maintained below 25-30° C. during this addition. After complete addition, the cooling bath was promptly removed and the mixture continued to stir at RT for 1 h. 5-Bromo-2-chloronicotinic acid (500 g, 2.115 mol) was then added to the slurry portion wise. The reaction mixture was heated to 115° C. overnight. The dark brown reaction mixture was cooled to 20° C. and diluted with water (2 L). The reaction mixture was acidified using HOAc (845 ml). The black homogenous solution (pH=5) was allowed to stir for 1 h at RT and poured slowly onto ice-water (20 L). The slurry was filtered at RT, washed with water (2×2 L) and dried in air to give 765 g of 5-Bromo-2-(4-iodophenoxy)-nicotinic acid as light orange solid. Step 2: A 5 L 3-neck flask equipped with an overhead stirrer, a thermometer and nitrogen inlet was charged with PPA (4 Kg, 1942 mL) (115% H3PO4) and heated to 115-120° C. 5-Bromo-2-(4-iodophenoxy)nicotinic acid (400 g, 952 mmol) was charged portion wise to the hot PPA. The viscous mixture was then allowed to stir overnight (16-18 h) at 115-120° C. The dark viscous mixture was cooled to 60-65° C. and poured slowly onto a mixture of ice (3000 g) and water (2000 mL) under mechanical stirring. The light brown slurry was allowed to stir overnight and filtered at RT. The wet cake was washed with water (2×1000 mL) followed by IPA (1500 mL) and hexane (2×1000 mL). The solid was dried to obtain 326.4 g of 3-Bromo-7-iodo-5H-chromeno[2,3-b]pyridine-5-one as a grey solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[ClH:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][SH:17]>C(N(CC)CC)C.CC(C)=O>[ClH:11].[ClH:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][S:17][C:4]1[C:5]([CH3:9])=[C:6]([OH:8])[C:7]([S:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])=[C:2]([CH3:1])[C:3]=1[OH:10]
Reactant: CN(C)CCCS
Reactant: CC1=CC(=O)C(C)=CC1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(O)c(SCCCN(C)C)c(C)c(O)c1SCCCN(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 27.2 g (0.200 mole) of 2,5-dimethyl-1,4-benzoquinone, 31.1 g (0.200 mole) of 3-(dimethylamino)propanethiol hydrochloride and six drops of triethylamine in 300 ml of acetone was stirred at ambient temperature for 15 hours. The cream-colored, crude, solid product was collected on a filter and recrystallized from methanol to give the pure product, 2,5-bis((3-(dimethylamino)propyl)thio)-3,6-dimethyl-1,4-benzenediol dihydrochloride, as cream-colored platelets, mp 254.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:32]([C:29]2[N:26]3[C:25]([S:24][CH:28]=[CH:27]3)=[N:31][CH:30]=2)=[O:33])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnc2sccn12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=498.3.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14])=[O:4].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[ClH:21]>C1(C)C=CC=CC=1.CCOCC>[ClH:21].[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14])=[O:4])[CH3:17]
Reactant: CCNCC
Reactant: CC(=O)c1cccc(C)c1NC(=O)CBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC)CC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 4.0 g of 2-bromo-2'-acetyl-6'-methylacetanilide in 60 ml of toluene was added 2.5 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature overnight. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol-ether gave 2-(diethylamino)-2'-acetyl-6'-methylacetanilide hydrochloride having a melting point of 141° to 143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([CH2:19][C:10]2[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=3)[CH:9]=2)[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)ccc1F
Yield: 98.6 %

Procedure:
Following the procedure of Example 1(10), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 98.6%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:8]=[CH:9][C:10]([Cl:15])=[C:11]([CH:14]=1)[C:12]#[N:13])[CH2:3][N:4]([CH3:6])[CH3:5].O[C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=2[N:20]=[N:21][N:22]=1>>[Cl:15][C:10]1[CH:9]=[CH:8][C:7]([C@H:2]([NH:1][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=3[N:20]=[N:21][N:22]=2)[CH2:3][N:4]([CH3:6])[CH3:5])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: CN(C)C[C@@H](N)c1ccc(Cl)c(C#N)c1
Product: CN(C)C[C@@H](Nc1nnnc2c(C(N)=O)cccc12)c1ccc(Cl)c(C#N)c1

Procedure:
Compound 17 was prepared following general synthetic scheme 7 wherein (S)-5-(1-amino-2-(dimethylamino)ethyl)-2-chlorobenzonitrile was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [397 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.81 (d, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.15 (d, 1H), 8.05-8.01 (m, 2H), 7.88 (dd, 1H), 7.72 (d, 1H), 5.78 (q, 1H), 2.95-2.89 (m, 1H), 2.62-2.58 (m, 1H), 2.24 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].[C:16]1([S:22](Cl)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.ClC(Cl)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:12]([S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:23])=[CH:11][C:9]=2[O:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2ccc(C)cc2O1
Reactant: O=S(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1Oc2cc(C)c(S(=O)c3ccccc3)cc2O1
Temperature: 0 °C

Procedure:
20.8 g (0.1 mol) of 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester Example 2b) and 19.2 g (0.125 mol) of phenylsulphinic acid chloride are dissolved in 200 ml of 1,2-dichloroethane and cooled to 5° using an ice-bath. 13.3 g (0.1 mol) of aluminium chloride are introduced in the course of approximately 15 minutes at from 5°-10° while stirring. The mixture is stirred for a further hour in the ice-bath and is then poured out onto ice-water. The resulting emulsion is diluted with 200 ml of dichloroethane and filtered across a layer of a filter aid (for example Hyflo). The filtrate is introduced into a separating funnel and the layers are separated. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness by evaporation. A light brown honey-like product, 5-phenylsulphinyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester, is obtained.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[NH:34]1[C:1]([CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=2)[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:30])[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=2)=[N:2][N:36]=[N:35]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccccc2Oc2cccc(OCC#N)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Oc2cccc(OCc3nnn[nH]3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
In 15 ml of N,N-dimethylformamide (DMF) was dissolved 1.5 g of N-[2-(3-cyanomethoxyphenoxy)phenyl]-4-hexyloxybenzamide followed by addition of 0.44 g of sodium azide and 0.37 g of ammonium chloride, and the mixture was stirred at 105°-110° C. for 1 hour. After cooling, the reaction mixture was diluted with ice-water and acidified with hydrochloric acid. The resulting precipitate was collected by filtration and recrystallized from ethanol to give 1.35 g of the title compound as white crystals, m.p. 158°-159° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[O:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9](=[O:10])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[OH:8]
Reactant: CN(C)CCCN
Reactant: O=C1CCc2ccccc2O1
Product: CN(C)CCCNC(=O)CCc1ccccc1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (1.40 g) was added to 3,4-dihydrocoumarine (2.01 g) and stirred for 0.5 hour at 70° C., thereby yielding the entitled compound (3.60 g) as white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([OH:51])=O)[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[C:53]1([CH:59]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C>[CH:59]([N:66]1[CH2:71][CH2:70][N:69]([C:49]([C:47]2[N:48]=[C:43]3[CH2:42][CH2:41][CH:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([O:32][CH3:31])=[C:34]([CH3:52])[CH:35]=4)[CH2:45][N:44]3[CH:46]=2)=[O:51])[CH2:68][CH2:67]1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCN(C(c5ccccc5)c5ccccc5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then diphenylmethylpiperazine (166 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was filtered. Yield: 232 mg (88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>>[C:2]1([NH:1][C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Product: CC(C)=CC(=O)Nc1ccccc1
Yield: 86 %

Procedure:
This is prepared analogously to a) from aniline and 3,3-dimethylacryloyl chloride. Yield 86% of theory; m.p. 124°-126° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]=[C:12]=[S:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[S:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CN=C=S)CC1
Reactant: Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CNC(=S)Nc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4 parts of 1-acetyl-4-(isothiocyanatomethyl)piperidine, 2.2 parts of 4-fluorobenzenamine and 90 parts of tetrahydrofuran was stirred overnight at reflux temperature. The reaction mixture was evaporated, yielding 6.2 parts (100%) of N-[(1-acetyl-4-piperidinyl)methyl]-N'-(4-fluorophenyl)thiourea as a residue (intermediate 12).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[Cl:1][C:2]1[C:3]([O:15][CH2:14][CH:13]([F:16])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OCC(F)F
Product: O=C(O)c1cnc(OCC(F)F)c(Cl)c1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (4.12 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[N:15]1C=CC=C[CH:16]=1>>[C:16]([C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8])#[N:15]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Reactant: c1ccncc1
Product: Cc1cc(-c2ccccc2)nnc1C#N

Procedure:
Add 1.25 g (6.1 mol) 3-chloro-4-methyl-6-phenyl pyridazine, 0.99 g (11.0 mol) cuprous cyanide and 20 mL pyridine into 50 mL pressure reaction tube, allow the mixture react for 24 hours at 130° C. then cool down and filtrate, and wash the cake three times with 50 mL ethyl acetate, and the organic phase is washed twice with 100 mL 1N HCl, following by drying with anhydrous sodium sulfate, and brown solid compound, crude product 2, is obtained after concentration, the crude product can be directly used in the next step reaction without further purification, MS: 196.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[NH:5][C:4](=[O:13])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH:22]=[CH2:23].C(Cl)(Cl)Cl>CN(C)C=O.O>[CH2:23]([O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH3:14])([CH3:1])[CH2:3][C:4](=[O:13])[NH:5]2)[CH:22]=[CH2:21]
Reactant: CC1(C)CC(=O)Nc2cccc(O)c21
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCOc1cccc2c1C(C)(C)CC(=O)N2
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.5 %

Procedure:
4,4-Dimethyl-5-hydroxy-3,4-dihydrocarbostyril (3.45 g, 18.0 mmol) was dissolved in dimethylformamide (100 ml). To the solution, potassium carbonate (2.99 g, 21.7 mmol) and allyl iodide (3.33 g, 19.9 mmol) were added, and the mixture was stirred at 100° C. for 24 hours. Subsequently, potassium carbonate (1.5 g, 10.9 mmol) and allyl iodide (1.65 g, 9.82 mmol) were added and stirring was continued for 24 hours. The reaction mixture was condensed under reduced pressure. Chloroform and water were added to the residue, and extracted. After the extract was dried and condensed, the residue was purified by silica gel column chromatography (developer=chloroform:methanol=50:1). Recrystallization from a solvent mixture of chloroform-hexane-ether yielded 2.06 g of the title compound as pale yellow needles (52.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:16][Si:17](Cl)([CH3:20])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:19][CH2:18][SiH:17]([CH3:20])[CH3:16]
Reactant: Oc1cccc(Br)c1
Reactant: CC[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[SiH](C)CCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-bromophenol (0.60 g, 3.47 mmol) in dry THF (15 mL) under nitrogen was added Et3N (0.48 mL, 3.47 mmol). A clear yellow solution formed immediately; after cooling to 0° C., dimethylethylsilyl chloride (0.43 g, 0.49 mL, 3.47 mmol) was added by syringe over a period of 10 minutes. The yellow color disappeared in 10 min, and a white cloudy solution formed. After 3 hr the thick reaction mixture was filtered, washed with 15 mL of hexane, and filtered again. Concentration gave a clear oil (quantitative weight recovery) that was used in the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2([OH:16])[CH2:15][CH2:14]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.ClCC[I:45]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:45])[N:8]2[CH2:11][CH2:12][C:13]2([OH:16])[CH2:15][CH2:14]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: ClCCI
Reactant: OC1(CCn2cnc3c(N4CCOCC4)nc(Cl)nc32)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(CCn2c(I)nc3c(N4CCOCC4)nc(Cl)nc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A solution of 1-(2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol (220 mg, 0.68 mmol) and N,N,N′,N′-tetramethylethylene-diamine (0.15 mL, 1.0 mmol) in THF (4.9 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (1.5 mL, 3.7 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.31 mL, 3.3 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 1-(2-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol as a colorless oil (220 mg, 71%). LC/MS (ESI+): m/z 450 (M+H)
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[NH:14])[S:10][CH:11]=1)=O.[N:16]#[C:17][NH2:18].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:12]([C:9]1[S:10][CH:11]=[C:7]([C:5]2[N:16]=[C:17]([NH2:18])[NH:3][CH:4]=2)[N:8]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(C(=O)CN)cs1
Reactant: N#CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N=C(N)Nc1nc(-c2c[nH]c(N)n2)cs1
Yield: 47.8 %

Procedure:
A mixture of 43 g (0.15 mol) of 2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride, 12.6 g (0.30 mol) of cyanamide, and 400 ml of water was brought to pH 4.5 by the dropwise addition of 20% sodium hydroxide solution. The mixture was heated at 50°-60° for 16 hours. The mixture was cooled, made basic with aqueous sodium carbonate solution and the resulting precipitate was collected by filtration, then washed successively with cold water, acetone, and ether. The dried solid was purified by dissolving in a minimum of dimethylformamide, then slowly adding ethyl acetate. Initially tarry material precipitated which was removed by decanting. Further addition of ethyl acetate afforded 16 g of a tan solid. This was again purified by the dimethylformamide-ethyl acetate procedure described above to give 12 g of a tan solid. Recrystallization of this material from methanol/water afforded analytically pure title compound as tan needles, mp 267° (dec.). Calcd. for C7H9N7S: C, 37.66; H, 4.06; N, 43.91; S, 14.36; found: C, 37.81; H, 4.31; N, 43.76.