Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]\1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:38]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:34][CH:33]=3)[N:37]=[CH:4][C:5]=2[CH2:14]1
Reactant: CN(C)/C=C1/C[C@@H](c2ccccc2F)c2ccccc2C1=O
Reactant: N=C(N)Nc1ccc(N2CCNCC2)cc1
Product: Fc1ccccc1[C@@H]1Cc2cnc(Nc3ccc(N4CCNCC4)cc3)nc2-c2ccccc21

Procedure:
This was synthesized by using (R,Z)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and 1-(4-(piperazin-1-yl)phenyl)guanidine as described in general procedure 1. LCMS m/e 452 (M+H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[C:18]2[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:19]=2[NH:20][CH:21]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:7][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[C:18]2[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:19]=2[NH:20][CH:21]=1
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3O)c2s1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]cc(C3CCCCC3F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Diethylaminosulfur trifluoride (1.2 eq.) was added at −60° C. to a 0.1M solution of methyl 6-(2-hydroxycyclohexyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry EtOAc, and the mixture was stirred at this temperature for 1 h, then allowed to warm slowly to RT. Aq. NaHCO3-solution was added and the mixture was extracted with EtOAc; the organic layer was washed with water and brine, dried on Na2SO4 and concentrated. Chromatography (PE/EtOAc) afforded the title compound (73%). 1H-NMR (300 MHz, CDCl3, 300 K, δ) 8.31 (bs, 1H), 7.67 (s, 1H), 7.06 (s, 1H), 4.53 (dtd, 1H, J 48.6, 10.1, 4.5), 3.88 (s, 3H), 2.88-2.77 (m, 1H), 2.41-1.17 (m, 8H); MS (ES+) m/z 282 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C-:30]#[N:31].[K+]>CN(C)C=O>[Br:20][C:18]1[CH:19]=[C:14]([C:5]2[C:6]3[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=3)[N:8]=[C:3]([CH2:2][C:30]#[N:31])[C:4]=2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=[N:16][CH:17]=1
Reactant: CCOC(=O)CCCCc1c(CBr)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(CC#N)nn2c(CC)ccc2c1-c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 45.9 %

Procedure:
A mixture of ethyl 5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (70.0 mg) and potassium cyanide (13.1 mg) in N,N-dimethylformamide (1 mL) was stirred for 28 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times), brine, dried over magnesium sulfate, and evaporated to give ethyl 5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow gum (28.8 mg, 45.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(F)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(F)cccc1Cl
Yield: 91106.6 %

Procedure:
To a solution of 2-chloro-6-fluorobenzamide (2.0 g, 0.011 mmol) in EDC (10 mL) was added oxalyl chloride (2.18 g, 0.017 mmol). The reaction mass was refluxed for 24 h. Excess of solvent was removed under vacuum to afford 2.0 g of desired product.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[Cl:5][C:6]1[CH:11]=C(Cl)N2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1>C(O)C>[Cl:5][C:6]1[CH:11]=[C:2]([SH:3])[N:1]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1
Reactant: NC(N)=S
Reactant: Clc1cc(Cl)n2ncnc2n1
Solvent: CCO
Product: Sc1cc(Cl)nc2ncnn12
Yield: 28.9 %

Procedure:
Thiourea (1.7 g) was added all at once to a solution of 4.2 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine in 140 ml anhydrous ethanol at room temperature, the mixture was refluxed for 30 minutes, the crystals formed upon ice cooling were filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 18 ml of 1N sodium hydroxide solution. The resulting solution was washed with 20 ml of ethyl acetate. The pH was adjusted to 1.0 with concentrated hydrochloric acid to give crystals. The crystals were collected by filtration and washed with 20 ml of water and then with 20 ml of methanol, affording 1.2 g of the objective compound as faint yellow crystals.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([NH:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC(=O)c2ccccc2)cc1

Procedure:
1-Benzoyl-2-(4-nitrophenyl)hydrazine (14.3 g, 0.056 mole) and 10% palladium/charcoal (catalytic amount) were suspended in ethanol (300 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a tan crystalline powder. Yield 11.5 g (90%), m.p. 134°-136° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][N:6]([C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:27][C:26]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]1=2
Reactant: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21

Procedure:
[2-[[3-(Dimethylamino)propyl](3-amino-2-pyridinyl)amino]phenyl]phenylmethanone from Example 21a is refluxed in excess acetic acid or in toluene solution containing a catalytic amount of p-toluene sulfonic acid to give a solution of the title compound.
Reaction SMILES: [CH:1]1([P:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:33][S:34](O)(=[O:36])=[O:35].[OH-].[Na+:39]>CO>[CH:24]1([P:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([S:34]([O-:36])(=[O:35])=[O:33])[C:15]=2[O:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1.[Na+:39]
Reactant: O=S(=O)(O)O
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added 2-dicyclohexylphosphino-2′6′ dimethoxybiphenyl (5.13 g, 12.5 mmol) and CH2Cl2 (5 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (32.5 mL, 625 mmol) was added dropwise. The solution slowly turned yellow in color. The solution was heated to 40° C. in a preheated oil bath and was allowed stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜50 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜200 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×300 mL) and concentrated under reduced pressure to give a light yellow solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (2) as a light yellow solid (6.35 g, 99%). Mp=165° C. (turned red, dec.) 1H NMR (400 MHz, CD3OD) δ: 7.88 (d, 1H, J=8.8 Hz), 7.60 (m, 1H), 7.36 (m, 2H), 7.22 (m, 1H), 6.76 (d, 1H, J=8.8 Hz) 3.70 (s, 3H), 3.39 (s, 3H), 1.14-2.01 (m, 22H). 13C NMR (125 MHz, CD3OD) δ: 161.3, 157.1, 143.3, 142.9, 137.9, 137.8, 133.7, 133.6, 133.3, 133.2, 131.9, 130.0, 129.3, 128.0, 127.9, 127.8, 105.9, 61.6, 56.1, 50.0, 37.0, 36.9, 34.8, 34.6, 31.7, 31.6, 31.5, 31.2, 31.0, 30.8, 30.7, 28.9, 28.8, 28.7, 28.4, 28.34, 28.31, 28.2, 27.8, 27.7. 31P NMR (162 MHz, CD3OD) δ: −8.02. IR (neat, cm−1): 3453, 2925, 2849, 1577, 1462, 1448, 1400, 1229, 1191, 1099, 1053, 736. Anal. Calcd for C26H34NaO5PS: C, 60.92; H, 6.69. Found: C, 60.40; H, 6.85. 1H NMR (d4-MeOH/D2O) is shown in FIG. 7. 31P NMR (d4-MeOH) is shown in FIG. 7.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21].Cl>CN(C)C=O>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:19][C:20](=[O:22])[CH3:21])=[O:4]
Reactant: CC(=O)CCl
Reactant: CCCCCC(Br)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(Br)C(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
2-Bromoheptanoic acid (86.0 g, 411.3 mmol) is placed in 600 ml of dimethylformamide, 49.95 g (493.6 mmol) of triethylamine are added dropwise thereto within 5 minutes at 20° C. and the pale yellow solution is stirred at room temperature for 15 minutes. Chloroacetone (57.07 g, 617 mmol) is added dropwise during 30 minutes and the yellow-brown suspension is stirred at room temperature for 90 minutes. The reaction mixture is poured on to 1 l of 1N HCl and ice and extracted in a separating funnel with 3×500 ml of ether. The organic phases are washed with 2×200 ml of water, dried over MgSO4 and concentrated on a rotary evaporator. Distillation at 86°-88° C./0.05 mbar yields 80.56 g (73.9%) of acetylmethyl 2-bromoheptanoate.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].C1COCC1.B(F)(F)F.CCOCC>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH2:7][C:6]1([C:5]2[CH:8]=[CH:9][C:2]([C:1]#[N:10])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(C#N)cc1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(C2(N)CC2)cc1
Reaction time: 0.75 h
Yield: 15 %

Procedure:
Terephthalonitrile (500 mg, 390 mmol) was dissolved in 10 ml of DCM. Ti(OiPr)4 (1.1 ml, 3.9 mmol) was added to the solution, followed by a 3M solution of ethylmagnesium bromide in THF (2.3 ml, 7.0 mmol). The mixture was aged for 45 min at RT and BF3.Et2O (890 ul, 7.0 mmol) was added. The mixture was then aged for an additional 2 h at RT. The reaction was quenched with NH4Cl and 3N HCl. The layers were separated and the aqueous layer was washed with ether. The aqueous layer was then basicified using 10N NaOH (pH 9-10). EtOAc was added and the biphasic mixture was filtered. The layers were cut and the aqueous layer extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. Yield=15%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=3)[C:15]#[N:16])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.C(OCC)(=O)C.N.[Ni]>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH2:15][NH2:16])[CH:17]=[CH:18][N:19]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(N2CCN(C3CCCC3)CC2)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1ccnc(N2CCN(C3CCCC3)CC2)c1

Procedure:
A solution of 2.8 g (11 mmol) 2-(4-cyclopentyl-piperazin-1-yl)-isonicotinonitrile in 10 ml methanol, 15 ml ethyl acetate and 5 ml ammonia was hydrogenated over Raney Nickel with 1 bar hydrogen at 30° C. for 4 h. The mixture was filtered and the residue was washed with 20 ml ethyl acetate three times. After evaporation of the organic phase the residue was purified with preparative HPLC on reversed phase to yield after evaporation of the combined product fractions 1.21 g (42%) of the title compound as yellow solid. (m/e): 261.3 (MH+; 100%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[N:18][CH:19]=1.[I:21]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:13][C:14]1[C:15]([I:21])=[CH:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: II
Reactant: Clc1ccc(Br)cn1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1cc(I)c(Br)cn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 12 ml (83 mmol) diisopropylamine in 80 ml dry tetrahydrofuran 52 ml of a solution of n-butyllithium in hexanes (1.6 M, 83 mmol) was added at −78° C. over a period of 15 min under argon. The mixture was stirred at −78° C. for 10 min. A solution of 15.2 g (79.0 mmol) 5-bromo-2-chloro-pyridine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed −70° C. After completed addition the reaction mixture was stirred at −78° C. for 5 h. A solution of 24 g (95 mmol) iodine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed −70° C. The reaction mixture was stirred for another 30 min at −78° C. The reaction mixture was allowed to warm to −10° C. and treated with 120 ml of an aqueous solution of sodium thiosulfate (1 M, 120 mmol). The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were washed twice with saturated ammonium hydroxide solution, dried with sodium sulfate and concentrated. The residue was dissolved in hot heptane and allowed to stand over night. Filtration of the precipitate and drying in vacuo gave 19.3 g (77%) of the title compound as a light brown solid.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:20][CH2:19][CH2:18][S:17]1(=[O:22])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[O:21]=[S:17]1(=[O:22])[CH2:18][CH2:19][CH2:20][C:16]1=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)c1ccc(C(Cl)C2CCCS2(=O)=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)c1ccc(C=C2CCCS2(=O)=O)cc1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Ethyl 2-{4-[chloro-(1,1-dioxotetrahydro-1λ6-thiophen-2-yl)methyl]phenyl} propionate (420 mg) obtained in Example 39 was dissolved in benzene (7.0 ml), and to the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 ml), and the mixture was stirred for 3 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (300 mg, 79%).
Reaction SMILES: Cl.[CH2:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH2:3][CH3:4].N1C=CC=CC=1.[CH3:19][C:20](OC(C)=O)=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[NH2:12][C:7]1[CH:6]=[C:5]([CH2:2][CH2:3][CH3:4])[N:10]=[CH:9][C:8]=1[NH:11][C:20](=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(N)c(N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCc1cc(N)c(NC(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-propyl-pyridine-3,4-diamine hydrochloride (prepared from ethyl butyrylacetate as described in Example 28, steps 1-9) (187 mg, 1.00 mmol) in CH2Cl2 (4 mL) at 0° C. under N2 is added pyridine (0.24 mL, 3.00 mmol) followed by DMF (2 mL) (for solubility). Next, Ac2O (0.104 mL, 1.1 mmol) is added. The reaction mixture is stirred for 3 h while slowly warming to rt. It is then poured into saturated aq NaHCO3 and extracted thrice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated to 114 mg of crude N-(4-amino-6-propyl-pyridin-3-yl)-acetamide, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ 8.73 (br, 1H), 8.00 (s, 1H), 8.43 (s, 1H), 4.63 (br, 2H), 2.54 (m, 2H), 2.13 (s, 3H), 1.63 (sextet, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 194 [M+1].
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1.C(OCC)C>[C:5]12([CH2:4][CH2:3][NH:2][CH3:1])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: CNC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCCC12CC3CC(CC(C3)C1)C2
Yield: 61.8 %

Procedure:
A solution of 1-adamantaneacetic acid N-methylamide (1.54 g, 7.45 mmol) in tetrahydrofuran (15.0 ml) was added dropwise to a solution of lithium aluminum hydride (569 mg, 15.0 mmol) in diethyl ether (34.0 ml) under ice-cooling over five minutes. The mixture was refluxed for six hours and then stirred under ice-cooling again. Ethyl acetate was added to the reaction mixture to treat excess lithium aluminum hydride, and then the whole was extracted with 1 N hydrochloric acid (50 ml) twice. A 4 N aqueous sodium hydroxide solution was added to the extract to basify it, and the whole was extracted with diethyl ether (80 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (60 ml) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 890 mg (66%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([Cl:14])=[N:16][CH:17]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(Cl)nc2)c1=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (2.0 g, 11.0 mmol), 6-Chloro nicotinic acid (1.86 g, 11.8 mmol) in methanol (40 ml) were cooled to 0° C. and added EDCI.HCl (4.2 g, 22 mmol). The reaction mixture was stirred at 25° C. for 20 hours and the solvents were removed under reduced pressure. To this residue water (20 ml) was added and the precipitate was filtered off, and washed sequentially with cold water (20 ml) and methanol (5 ml) to obtain N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide as an off white solid. (2.47 g, 70%).
Reaction SMILES: [P:1](Cl)([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O:3][CH3:4])=[O:2].[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2)([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O:3][CH3:4])=[O:2]
Reactant: COP(=O)(Cl)Sc1cccc([N+](=O)[O-])c1
Reactant: O=C1CCc2cccc(O)c21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(=O)(Oc1cccc2c1C(=O)CC2)Sc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Methyl S-(3-nitrophenyl) chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-methyl S-(3-nitrophenyl) O-indan-1-on-7-yl thiophosphate.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:11])OCC)=S)[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClC1N=C(OCC)[N:22]=[C:21]([N:28]([CH3:30])[CH3:29])[N:20]=1.[Na].C(=O)([O-])N.ClC1N=C(Cl)N=C(N(C)C)N=1>O.C(O)C>[CH3:29][N:28]([CH3:30])[C:21]1[N:22]=[C:4]([O:3][CH2:1][CH3:2])[NH:6][C:7](=[O:11])[N:20]=1
Reactant: CCOc1nc(Cl)nc(N(C)C)n1
Reactant: CCOC(=O)NC(=S)OCC
Agent: CN(C)c1nc(Cl)nc(Cl)n1
Agent: NC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOc1nc(N(C)C)nc(=O)[nH]1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
Ethyl ethoxythiocarbonylcarbamate (1 molar proportion) was added to a stirred solution of potassium carbonate in water (10 ml. per gram of carbamate). After 15 minutes stirring, the solution was filtered and dimethyl sulphate added dropwise to the filtrate with vigorous stirring over 45 minutes. The mixture was then stirred for 1 hour and extracted with light petroleum. The extracts were dried and cooled to -40° C., when the carbamate separated. Recrystallised from petroleum, the carbamate had a melting point of 38°-39° C. (b) N,N-Dimethylguanidine hydrochloride (3.23 g; 0.026 mol.) was added to a solution of sodium (0.61 g; 0.026 mol.) in anhydrous ethanol (50 ml.) and the mixture was heated under reflux for 30 minutes. The carbamate prepared in (a) above (5.0 g., 0.026 mol.) was then added and the mixture heated under reflux for 22 hours. The ethanol was removed, water (75 ml.) added, and the pH of the solution adjusted to 6 to 7 with acetic acid. The product was collected, washed with water, and recrystallised from ethanol to give 4-dimethylamino-6-ethoxy-1,3,5-triazin-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([N+:18]([O-])=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O)(=O)C.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2].O>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([NH2:18])=[CH:13][CH:12]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2cc3cc([N+](=O)[O-])ccc3[nH]2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc3cc(N)ccc3[nH]2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(3,5-dimethylphenyl)-5-nitro-1H-indole (2 g in a mixture of 55 mL tetrahydrofuran and 20 mL methanol) was added 347 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (1 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 25 hours the flask was charged with an additional 320 mg catalyst and 1 mL of 30% acetic acid and re-subjected to hydrogen. After a total reaction time of 3 days, the mixture was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (hexane:ethyl acetate, 1:1) gave the title compound (1.16 g).