Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:38]2[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=3[N:34]=[CH:35][N:36]=2)[CH:7]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: COc1cccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)c1
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: COc1cccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4ncccc34)c2)c1
Yield: 45 %

Procedure:
The product from Example 31A and the product from Example 57A were reacted according to the procedure in Example 57E substituting the product of Example 31A for the product of Example 57D to provide a solid which was triturated with methanol to provide the title compound (38 mg, 45%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.86 (d, J=7.72 Hz, 1H), 8.59 (s, 1H), 7.64 (s, 1H), 7.23-7.36 (m, 2H), 7.16 (dd, J=8.64, 1.65 Hz, 1H), 7.07-7.13 (m, 2H), 6.93-7.05 (m, 3H), 6.89 (dd, J=8.27, 2.02 Hz, 1H), 6.61-6.71 (m, 2H), 5.08 (s, 2H), 3.75 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI−) m/z 481.2 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:16])[CH:11]=[CH:12][CH:13]([CH3:15])[CH3:14].[H][H].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:16])[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)c(C(=O)CCC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
Undernitrogen, 2.8 g of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone was dissolved in ethyl acetate and 0.14 g of 5% palladium/carbon was added thereto. The nitrogen in the reaction vessel was substituted by hydrogen and the reaction mixture was stirred at room temperature for 5 hours. After that, the reaction mixture was filtered through a Celite pad and the Celite pad was washed with 50 ml of ethyl acetate. The solution combined the filtrate with the washing solution was washed with 0.1% hydrochloric acid once, water twice and saturated brine once, subsequently. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to give 2.68 g of 4-hydroxy-6-methyl-3-(4-methylpentanoyl)-2-pyrone.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCCOC(=O)c1cc(N)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (4.4 g, 0.037 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.25 g, 0.033 mole) and methylene chloride (50 ml). The mixture was warmed to a gentle reflux for 3 hours, stirred overnight at room temperature, and evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2- methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml), chilled, and treated dropwise over about 2 hours with a solution of propyl 5-amino-2-chlorobenzoate (7.0 g, 0.033 mole) and triethylamine (3.5 g, 0.035 mole) in methylene chloride (50 ml).
Reaction SMILES: CC1C=CC(S(O[CH:12]([CH2:29][CH3:30])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH:15]1([CH2:14][C@H:13]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]([NH:32][CH3:31])[CH2:29][CH3:30])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN
Reactant: CCC(OS(=O)(=O)c1ccc(C)cc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Product: CCC(NC)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
A solution of (S)-2-(tert-butoxycarbonylamino)-1-cyclohexylpentan-3-yl 4-methylbenzenesulfonate (640 mg, 1.46 mmol) in 33% MeNH2 (in EtOH) (0.02 M) was heated to 60° C. for 1 h in a pressure sealed vessel. The solvent was removed under reduced pressure to give (S)-tert-butyl 1-cyclohexyl-3-(methylamino)pentan-2-ylcarbamate. MS ESI +ve m/z 299 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[C:11](=[O:20])[C@@H:12]([CH3:19])[C@H:13]([C:16]([CH3:18])=[CH2:17])[CH2:14][CH:15]=1.CN(P(N(C)C)(N(C)C)=O)C.CS(O[CH2:37]/[CH:38]=[CH:39]\[I:40])(=O)=O.C([O-])(O)=O.[Na+]>CCOCC>[CH3:9][C:10]1[C:11](=[O:20])[C@@:12]([CH3:19])([CH2:37]/[CH:38]=[CH:39]\[I:40])[C@@H:13]([C:16]([CH3:18])=[CH2:17])[CH2:14][CH:15]=1
Reactant: CS(=O)(=O)OC/C=C\I
Reactant: C=C(C)[C@@H]1CC=C(C)C(=O)[C@H]1C
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: C=C(C)[C@H]1CC=C(C)C(=O)[C@@]1(C)C/C=C\I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.9 %

Procedure:
To a cold (−40° C.) solution of 46 mL (21 numol) of LDA (prepared as mentioned above from 2.9 mL of diisopropylamine and 13 mL of n-BuLi in 30 mL of THF) under argon was added a solution of 1.69 g (10.3 mmol) of (5R,6S)-2,6-dimethyl-5-isopropenyl-2-cyclohexen-1-one in 30 mL of ether was added via cannula, and the resulting solution was stirred at 0° C. for 45 min. To it, 1.8 mL (10 mmol) of HMPA was added, stirred at the same temperature for 4 hours, and a solution of 5.68 g (22 mmol) of (cis-3-iodo-2-propenyl) methanesulfonate (40)2 in 30 mL of ether was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into an aqueous solution of NaHCO3, extracted three times with ether, and the combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was column chromatographed on silica gel using a hexane:methylene chloride (3:2) as eluant to give 2.48 g (73% yield) of 41 and 0.237 g (14% recovery) of the starting material.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C1CCNC1
Product: [C-]#[N+]CC(=O)N1CCCC1
Yield: 98 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 5.0 g, 47.8 mmol) was slowly added in 0.75 h pyrrolidine (6.5 mL, 78 mmol). The mixture was stirred for 1.5 h with continued cooling and then concentrated. The resulting oil was co-evaporated twice from CH2Cl2:hexane to remove residual pyrrolidine. 2-Isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 was obtained as a yellow solid (6.85 g, 98% yield) and used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][O:34][C:35](=[O:39])[CH:36](Br)[CH3:37]>>[CH3:33][O:34][C:35](=[O:39])[CH:36]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:32])[CH3:1])[N:26]([CH:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)[CH3:37]
Reactant: COC(=O)C(C)Br
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: COC(=O)C(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 38.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo propionic acid methyl ester (31 mL, 0.28 mmol) gave 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid methyl ester (46 mg, 39%). MS (ESI) m/z 521.4 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[O:23]C)[CH:6]=1)C>ClCCl>[Br:22][C:20]1[CH:19]=[CH:18][C:17]([OH:23])=[C:16]([C:12]2[CH2:13][CH2:14][CH2:15][C:11]=2[C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:25])=[O:3])[CH:21]=1
Reactant: CCOC(=O)c1cccc(C2=C(c3cc(Br)ccc3OC)CCC2)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(C2=C(c3cc(Br)ccc3O)CCC2)c1

Procedure:
3-{2-[5-Bromo-2-(methoxy)-phenyl]-cyclopent-1-enyl}-benzoic acid ethyl ester (416 mg, 10.0 mmol) in dichloromethane (5 mL) was cooled under nitrogen to ˜40° C. and was treated with a molar solution of borontribromide in dichloromethane (20 mL, 20.0 mmol). The reaction mixture was then allowed to reach room temperature and kept stirring over night. The reaction mixture was then quenched with ice/water (50/50 mL) and more dichloromethane (30 mL) was added. After stirring vigorously for 1.5 hr. the organic layer was separated, dried (magnesium sulphate), evaporated down and chromatographed with 1% methanol in dichloromethane to give (300 mg, 80%).
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:3].[CH2:17]([O:19][N:20]=[CH:21][CH3:22])[CH3:18].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:17]([O:19][N:20]1[CH:21]([CH3:22])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:18]
Reactant: C=C(C)C1CCCCCCCCCCC1=O
Reactant: CC=NOCC
Agent: CCON1C(=O)CCCCCCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCCCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclododecanone (2.00 g, 9.02 mmol), acetaldehyde O-ethyl oxime (1.18 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (2.45 g, 88% yield). Mixture of E/Z isomers in a ratio of 2:1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=[C:11](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[CH2:42]Br)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[CH2:42][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:10]=[C:11](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=3)=[CH:4][CH:3]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(O)cc2)n1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Product: CCOC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n1
Yield: 48.9 %

Procedure:
According to the procedure for preparation of 4.4, phenol 13.3 (73 mg, 0.206 mmol) was alkylated with (4′-chloro-4-methoxy-1,1′-biphenyl-2-yl)methyl bromide (71 mg, 0.227 mmol), to yield 59 mg (49%) of 13.4. MS (ESI) 585.4 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[CH3:23]I>COCCOCCOC>[CH3:19][C:17]1[CH:18]=[C:13]2[N:12]([CH3:23])[C:11](=[O:20])[C:10]3[CH:9]=[N:8][C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=4[C:15]=3[N:14]2[N:16]=1
Reactant: CI
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n(C)c3cc(C)nn3c12
Reaction time: 10 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) are added to a suspension of 0.03 g. of sodium hydride in 50 ml. of diethylene glycol dimethyl ether at reflux temperature. The temperature is maintained for one hour and then lowered to 120°. 2.8 g. of methyl iodide are added and heating is continued for 10 hours. The precipitated sodium iodide is filtered off, the solution evaporated to dryness and the residue recrystallized from ethyl-acetate, yield 1.9 g. (68%); m.p. 206°-207°.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[F:47][C:48]1[N:53]=[CH:52][C:51]([NH:54][NH2:55])=[CH:50][CH:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:51]3[CH:52]=[N:53][C:48]([F:47])=[CH:49][CH:50]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1ccc(F)nc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1

Procedure:
500 mg (1.16 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 284 mg (1.74 mmol) of 6-fluoropyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 256 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:7][O:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:8]2[CH2:7][O:6][CH2:5][C@H:4]2[NH2:1])=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A solution of cis-3-azido-4-(4-bromophenoxy)tetrahydrofuran (286.7 g, 1.01 mol) in tetrahydrofuran (1.25 L) was cooled to 0° C. and treated with triphenylphosphine (278 g, 1.06 mol). The reaction was allowed to warm to room temperature and stirred for 18 hours. Water (53 mL) was added and the reaction was stirred at room temperature for 66 hours. Solvent was removed under reduced pressure and the residue was mixed with diethyl ether. The supernatant was decanted and concentrated in vacuo, providing a residue, which was filtered through a short plug of silica gel (Gradient: 0% to 5% methanol in methylene chloride) to afford cis-4-(4-bromophenoxy)tetrahydrofuran-3-amine (155 g) and 366 grams of impure product. An acid/base extraction was carried out on the impure material, providing additional product (48.5 g). Total yield: 203.5 g, 0.788 mol, 68% over four steps. 1H NMR (300 MHz, CDCl3) δ 3.6 (m, 1H), 3.7 (m, 1H), 3.9 (m, 1H), 4.0 (m, 1H), 4.1 (m, 1H), 4.6 (m, 1H), 6.8 (m, 2H), 7.3 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH:23]C(=O)C(C)(C)C)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C(Cl)(Cl)Cl.CO>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH2:23])[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cccc(Nc2nc(N)nc3[nH]c4ccccc4c23)c1
Yield: 92 %

Procedure:
Using the general procedure described above, the reaction of 8 (90 mg, 0.23 mmol) and 1 N NaOH provided 65 mg of AAG104 as a transparent solid in 92% yield. TLC Rf 0.34 (chloroform-methanol 15:1); mp 225.2-225.6° C.; 1H NMR (DMSO-d6) δ 3.74 (s, 3H, OCH3), 6.05 (s, 2H, NH2, exch), 6.88-8.07 (m, 8H, Ar—H), 8.16 (s, 1H, 4-NH, exch), 11.20 (s, 1H, 9-NH, exch). Anal. Calculated (C17H15N5O. 0.15 (C2H5)2O): C, 66.79; H, 5.25; N, 22.13. Found: C, 66.77; H, 5.08; N, 22.13.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.CN(C)C=O.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)[CH:20]=[CH:19][N:18]=1
Reactant: OCC1(CO)CCC1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCC1(COc2ccnc(Cl)n2)CCC1
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 1.00 g (8.62 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 20 ml of (1:1) tetrahydrofuran:dimethylforamide was added a 60% dispersion of 0.413 g (8.62 mmol) of sodium hydride in oil. The reaction was stirred for 15 min and 1.28 g (8.62 mmol) of 2,4-dichloropyrimidine was added. After stirring for 2 h, the reaction was concentrated under vacuum and the residue was purified using silica gel chromatography eluting with ethyl acetate:hexane (4:6) to afford 0.9 g (51%) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=6 Hz, 1H), 6.69 (d, J=7 Hz, 1H), 4.51 (s, 2H), 3.67 (s, 2H), 2.35 (br s, 1H), 2.05-1.87 (m, 6H).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1>C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cccc(Br)c1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine is converted to the free base (4.9 g.; 0.05 mole) in benzene in the usual manner. Then 9.9 g. (0.05 mole) of m-bromophenylisocyanate [made according to the method of K. Inuaki and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added. The reaction mixture is stirred at room temperature for 11/2 hours and the solvent then evaporated in vacuo to give a solid residue of 1-(3-bromophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 138°-140° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:4][CH2:3]1.O.NN.Cl>C(O)C.CO>[NH2:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CO
Solvent: O
Product: CN1CCN(CCCN)CC1
Temperature: 25 °C

Procedure:
A solution of N-(3-(4-methylpiperazin-1-yl)propyl)phthalimide and hydrazine monohydrate in ethanol and methanol was refluxed for 4 hours. After cooling to room temperature, concentrated HCl was added and the mixture heated under reflux for another hour. After removing the solvent, water was added, the mixture stirred, and insoluble material removed by filtration. Solid K2CO3 and CH2Cl2 were added to the aqueous layer, the mixture stirred, and was then filtered. The organic layer was washed with water. The combined aqueous layers were washed with Et2O. Water was removed from the organic layers, they were then dried and evaporated to give 1-(3-aminopropyl)-4-methylpiperazine as an oil. A reference for this synthesis is Hou et al., “Efficient syntheses of oncinotine and neooncinotine,” J. Org. Chem. 69(18):6094-9, 2004, which is incorporated by reference herein.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C[OH:10].[CH3:11][NH:12][C@@H:13]1[CH2:22][C:21]2[C:16]3=[C:17]([NH:23][C:24](=[S:25])[N:15]3[CH2:14]1)[CH:18]=[CH:19][CH:20]=2>C(Cl)Cl>[C:1]([OH:8])(=[O:7])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10].[CH3:11][NH:12][C@@H:13]1[CH2:22][C:21]2[C:16]3=[C:17]([NH:23][C:24](=[S:25])[N:15]3[CH2:14]1)[CH:18]=[CH:19][CH:20]=2
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CO
Agent: CN[C@@H]1Cc2cccc3[nH]c(=S)n(c23)C1
Solvent: ClCCl
Product: O=C(O)CC(O)C(=O)O

Procedure:
A mixture of maleic acid (0.317 g, 2.36 mmol) in a minimal amount of methanol (˜1 mL) is added to a mixture of (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (EXAMPLE 8, 0.493 g, 2.25 mmol) in methylene chloride. The resulting solid is collected by filtration to give the title compound, mp=195-196°; [α]25D=−60° (c 0.93, methanol); IR (drift) 3140, 3112, 3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868 and 747 cm−1; NMR (300 MHz, CD3OD) 7.20-7.30, 7.10-7.20, 6.26, 4.49, 4.31, 4.05-4.20, 3.47, 3.28 and 2.83 δ; CMR (100 MHz, DMSO-d6+CD3OD) 170.4, 169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9, 43.1, 31.9 and 27.2 δ; MS (ESI, m/z) 220.1 (MH+).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:16]=[C:15]([C:25](OCC)=[O:26])[C:14]=2[CH3:30])=[CH:9][CH:8]=1.Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:35][O:34][N:33]([CH3:32])[C:25]([C:15]1[C:14]([CH3:30])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:16]=1)=[O:26]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
Isopropylmagnesium chloride (15 ml, 30 mmol) was added dropwise over a 10 to 15 minute period to a stirred solution of ethyl 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (8.15 g, 21.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) in THF at −25° C. After stirring for an additional 15 minutes at −25° C., the reaction mixture was quenched with saturated aqueous NH4Cl and then extracted with methyl-tert-butyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound I-1a as a golden oil (8.76 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[Cl:20].[I-].[Na+].[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>CCC(C)=O>[Cl:20][C:4]1[C:3]([CH2:2][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[N:8][C:7]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(Cl)c(CBr)n1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1nc(N2C(=O)c3ccccc3C2=O)ccc1Cl)OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Example 26 was dissolved in MEK (180 mL) and placed in a 500 mL flask under a N2 atmosphere. Sodium iodide (catalytic) was added to the reaction which was subsequently stirred at room temperature for 20 min. Triethyl phosphite (3.66 g, 22 mmol) was added to the reaction. The reaction was heated to reflux for 6 h, cooled to room temperature, and stirred an additional 16 h. The reaction was filtered and all solvent removed in vacuo to yield the crude title compound. Purification via flash chromatography (96/4 CHCl3 /EtOH) produced the pure title product.