Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:45][N:23]([C:24](=[O:44])[C@H:25]([C:40]([CH3:43])([CH3:42])[CH3:41])[NH:26][C:27](=[O:39])[O:28][C@@H:29]4[CH2:38][CH2:37][CH2:36][C@H:30]4[CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][C:10]=12)[C@H:22]([C:46]([O:48][CH3:49])=[O:47])[CH2:21]3)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[C:40]([C@H:25]1[C:24](=[O:44])[N:23]2[CH2:45][C@@H:20]([CH2:21][C@H:22]2[C:46]([O:48][CH3:49])=[O:47])[O:19][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]([OH:8])=[C:10]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:36][CH2:37][CH2:38][C@H:29]2[O:28][C:27](=[O:39])[NH:26]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCc1ccccc1)O2
Agent: [Pd]
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of methyl (3aR,7S,10S,12R,21E,24aS)-19-(benzyloxy)-7-tert-butyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxylate (synthesized as in Example 1 with intermediates B6 and C3) (1.16 g) in THF (8.7 ml) and methanol (8.7 mL) was added 10% Pd/C (92 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. The atmosphere was changed to nitrogen and the reaction was carefully filtered through celite to give 0.88 g of the desired product. LRMS (ES+) m/z 582.40 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(OC([N:37]([CH2:44][CH3:45])[C:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:41]([C:38]4([NH:37][CH2:44][CH3:45])[CH2:40][CH2:39]4)=[O:42])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCN(C(=O)OC(C)(C)C)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (67.3 mg, 0.17 mmol), 1-(tert-butoxycarbonyl(ethyl)amino)cyclopropanecarboxylic acid (38.0 mg, 0.17 mmol), HATU (63.0 mg, 0.17 mmol) and diisopropylethylamine (57 μL, 0.34 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the combined organic extracts were dried (Na2SO4) and then concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA and was then stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(ethylamino)cyclopropyl)methanone; ESMS m/z 527.2 (M+H+).
Reaction SMILES: O[Li:2].O.[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:43][C:44]([O:46]C)=[O:45])=[C:9]([CH:42]=1)[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>O.C1COCC1>[C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[C:5]([F:4])[CH:6]=[CH:7][C:8]=4[CH2:43][C:44]([O-:46])=[O:45])[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:15]=3)=[CH:28][CH:27]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:41])([CH3:39])[CH3:40].[Li+:2]
Reactant: COC(=O)Cc1ccc(F)cc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(F)ccc4CC(=O)[O-])n3)cc2)CC1
Product: [Li+]
Temperature: 40 °C

Procedure:
LiOH.H2O (0.063 g, 1.5 mmol) was added to a stirred solution of tert-butyl 4-(4-((4-(5-fluoro-2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A52) (0.092 g, 0.15 mmol) in H2O (0.5 mL) and THF (5 mL) and the resulting mixture heated at 40° C. overnight. The volatiles were removed in vacuo and the residue was taken up in DCM (50 mL). The resulting solution was washed with saturated aqueous Na2CO3 (25 mL) then the aqueous phase was then extracted with DCM (2×25 mL). The organic layers were combined, dried over MgSO4 and the volatiles were removed in vacuo to yield the title compound A53 (0.089 g, 98%); LCMS-A: rt 6.596 min; m/z 603 [(M-Li)+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:15]([O:17][CH3:18])=[O:16])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[O:22][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([O:17][CH3:18])=[O:16])([CH3:8])[CH3:10]
Reactant: COCCOCCl
Reactant: COC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C(=O)OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
2-Methoxyethoxy-methyl chloride (24.0 g, 192.7 mmol) is added dropwise to a 0° C. mixture of 25.0 g (94.6 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, methyl ester and 27.5 g (212.4 mmol) of diisopropylethylamine in 50 ml of CH2Cl2 under a nitrogen atmosphere. The reaction is stirred at 25° C. for 24 hours and then poured onto saturated aqueous NH4Cl and the layers are separated. The aqueous layer is extracted with t-butylmethyl ether (2×150 ml). The combined organic extracts are washed with saturated aqueous NH4Cl, water and brine (2×), dried over Na2SO4, and concentrated in vacuo to give 33.2 g of the desired product as an orange oil. The product is pure enough to use in subsequent reactions. A sample can be purified by chromatography (flash, SiO2, 230-400 mesh, 29×6.5 cm, 15% t-butylmethylether-hexane) followed by Kugelrohr distillation.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[F:13][C:14]([F:19])([F:18])C(O)=O>ClC1C=CC=CC=1Cl>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([C:14]([F:19])([F:18])[F:13])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1Cl
Product: COc1cccc2sc(C(F)(F)F)nc12

Procedure:
Starting from 2-amino-4-methoxybenzothiazole (1.5 g) and trifluoroacetic acid (5.5 ml), without 1,2 dichlorobenzene. Purification by flash chromatography (eluent 20% ethyl acetate/hexane) yielded the title compound as a light brown oil (0.74 g). TLC Rf 0.70 (50% ethyl acetate in hexane)
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:15])=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].O=P(Cl)(Cl)Cl>CN(C=O)C.O>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:15])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCC(c2cccc(C(N)=O)c2)CC1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C#N)c2)CC1
Yield: 39.1 %

Procedure:
A solution of 3-(1-propyl-piperidin-4-yl)-benzamide (350 mg) and POCl3 (326 μL) in dry DMF (6 ml) was heated at 80° C. for 3 h under an argon atmosphere. Evaporation of the solvent yielded a dark, oily residue, which was dissolved in water. The solution was basified and extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. The oily residue was chromathographed on a silica column with MeOH:CH2Cl2 (1:19 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 3-(1-Propyl-piperidin-4-yl)-benzonitrile (127 mg). The amine was converted into the fumarate salt and recrystallized from ethanol/diethylether: m.p. 122° C.; MS m/z (relative intensity, 70 eV) 228 (M+, 2), 199 (42), 129 (26), 70 (bp) 56 (53).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[NH:24][C:23]4[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=4[N:17]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:24]([CH3:33])[C:23]4[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=4[N:17]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4ccc(F)cc4)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)n2C)n(CCC)c1=O
Temperature: 50 °C

Procedure:
A mixture of 8-{1-[3-(4-fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (0.035 g, 0.08 mmol), potassium carbonate (0.022 g, 0.16 mmol), methyl iodide (0.005 ml, 0.088 mmol) and DMF (2 ml) were heated at 50° C. for 20 hour. The mixture was cooled to room temperature and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and sat. brine solution, and dried over Na2SO4. Solvent was evaporated, the residue obtained was triturated with hexane to obtain the title compound (0.022 g, 61
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23]Br)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:14]([O:18][C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=Cc1ccc(O)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2c1CCCC2
Yield: 59.8 %

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.6 g, 29.1 mmol) (3-Bromopropyl)-carbamic acid tert-butyl ester (110, 4.6 g, 32 mmol), and potassium carbonate (6.03 g, 43.7 mmol) were stirred in 140 mL of dry DMF over night. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine., dried with magnesium sulfate, filtered, concentrated and purified by flash chromatography (0-30% EtOAc/hexane) to give crude product, which was recrystallized from EtOAc/Hexane to give 5.8 g of 111, [3-(4-formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[S:15])([CH3:3])[CH3:2].Cl.C([O:19][C:20](=O)[CH2:21][NH:22][CH3:23])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:20](=[O:19])[CH2:21][N:22]([CH3:23])[C:14]1=[S:15])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNC
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)CN(C)C1=S
Yield: 60.2 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 8.3 g of 2,6-diisopropylphenyl-isothiocyanate, 5.8 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether/hexane mixture afforded the title compound (6.6 g) as a tan solid, m.p. 174°-176° C. Anal. Calcd. for C16H22N2OS: C, 66.17; H, 7.63; N, 9.64. Found: C, 66.39; H, 7.63; N, 9.59. Mass spectrum (+FAB, [M+H]+) m/z 269/271.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)C(=O)OC(C)(C)C)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CN1C(=O)CCC1>O>[ClH:1].[ClH:1].[ClH:1].[CH3:15][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:42]=[CH:41][C:23]([CH2:24][NH:25][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:22][CH:21]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N(CCN1CCOCC1)Cc1ccc(N)cc1
Reactant: Cc1cccc(Nc2nc(Cl)ncc2C(N)=O)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Nc2nc(Nc3ccc(CNCCN4CCOCC4)cc3)ncc2C(N)=O)c1
Product: Cl
Temperature: 130 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A mixture of 1.0 g of 2-chloro-4-(3-methylanilino)pyrimidine-5-carboxamide, 1.6 g of tert-butyl 4-aminobenzyl(2-morpholin-4-ylethyl)carbamate, 1.33 ml of diisopropylethylamine and 10 ml of NMP was stirred overnight at 130° C. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol). Then, a 750 mg portion of 780 mg of the resulting compound was stirred overnight at room temperature in a mixed solution of 75 ml methanol and 30 ml 6 M hydrochloric acid. The reaction mixture was concentrated, and then the resulting crystals were washed with methanol to obtain 510 mg of 4-[(3-methylphenyl)amino]-2-[(4-{[(2-morpholin-4-ylethyl)amino]methyl}phenyl)amino]pyrimidine-5-carboxamide trihydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:25]([C:31]1[CH:32]=[N:33][C:34]([OH:37])=[N:35][CH:36]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:37][C:34]3[N:33]=[CH:32][C:31]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:36][N:35]=3)=[O:21])=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Cl)cc2)CC1
Reactant: CCCCCCc1cnc(O)nc1
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCc1cnc(OC(=O)c2ccc(OC(=O)[C@H]3CC[C@H](CCCCCC)CC3)cc2)nc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of p-(trans-4-hexylcyclohexylcarbonyloxy)-benzoyl chloride (3.9 g) dissolved in toluene was added to a solution of 5-hexylpyrimidin-2-ol (1.0 g) in pyridine (10 ml), followed by stirring at 60° C. for 2 hours, allowing the mixture to stand at room temperature overnight, adding water and toluene to the reaction mixture, separating the toluene layer containing the reaction product, washing the toluene solution twice with 6NHCl (30 ml), washing with water, washing 5 times with 2N NaOH (100 ml), finally washing with water till the washing water became neutral, drying the resulting toluene solution, distilling off low boiling mixture of solvent, etc. under reduced pressure, and recrystallizing crystals obtained from the residue from n-heptanol solvent to obtain the objective compound (2.0 g) (yield 73%), which had a C-N point of 53.3° C. and a N-I point of 125.3° C.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].[CH3:8][O-:9].[Na+].C([CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[CH:21]=1)C(OCC)=O)=O>C(O)(=O)C>[N+:1]([NH:4][C:5]1[NH:7][C:8](=[O:9])[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:13][N:6]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C=O)Cc1ccnc(OC)c1
Reactant: C[O-]
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(-c2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1

Procedure:
By a process similar to that of Example 5, reaction of nitroguanidine, sodium methoxide and ethyl 2-formyl-3-(2-methoxy-4-pyridyl)-propionate gave 2-nitroamino-5-(2-methoxy-4-pyridyl)-4-pyrimidone, m.p. 194°-5.5° (from aqueous acetic acid).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1.CCN(CC)CC>C(#N)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:18])([F:20])[F:19])[CH:9]=2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of (R)-3-methylpyrrolidine (1.000 g, 8.226 mmol), 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (1.72 g, 8.226 mmol) and Et3N (2.080 g, 2.865 mL, 20.56 mmol) in ACN was heated at 80° C. for 5 hours. The reaction was cooled to RT, quenched with water, the layers seperated and the aqueous layer was extracted with DCM. The combined organic layer was washed with 1M HCl to remove the unreacted amine. The organic layer was dried over Na2SO4, filtered and concentrated to give (S)-3-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (1.97 g, 7.184 mmol) MS 275.0 m/z (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[NH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[N:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[NH2:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ncncc2N)C1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
tert-butyl ((3S)-1-(5-amino-4-pyrimidinyl)-3-piperidinyl) carbamate. A mixture of (S)-tert-butyl piperidin-3-ylcarbamate (486 mg, 2.42 mmol), 5-amino -4-chloropyrimidine (262 mg, 2.02 mmol, Magical Scientific, Atchison, Kans.) and Cs2CO3 (988 mg, 3.03 mmol) in 2 mL of DMF was heated in a microwave at 150° C. for 45 min. The mixture was diluted with 50 mL of EtOAc and filtered through a pad of Celite. The filtrate was washed with 5 mL saturated NH4Cl (aq.) followed by 5 mL of brine. The organic solution was concentrated and purified by silica gel chromatography (60-100% EtOAc in hexanes) to give tert-butyl ((3S)-1-(5-amino-4-pyrimidinyl)-3-piperidinyl)carbamate (233 mg, 39% yield, 90% purity). This material used without further purification. MS (ESI, pos. ion) m/z: 294.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31]Br)[C:14]1=[O:33])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(OC(C)C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31][N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[C:14]1=[O:33])=[O:11]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCBr)C1=O)c1cc2ccccc2[nH]1
Reactant: CN1CCNCC1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1

Procedure:
A mixture of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino) -1-(2-bromoethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.3 g) and 1-methylpiperazine (3.0 ml) was stirred for 4.0 hours at room temperature aND diisopropyl ether (20 ml) was added thereto. The resultant precipitates were collected by filtration and dissolved in diluted hydrochloric acid. The solution was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the resultant precipitates were collected by filtration to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[2-(4-methyl-1-piperazinyl)ethyl]-5-phenyl-2H-1,4-benzodiazepine-2-one (0.20 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[N:11]=[N:10][C:9](Cl)=[CH:8][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[NH2:22][NH2:23]>C(O)C>[C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[N:11]=[N:10][C:9]([NH:22][NH2:23])=[CH:8][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C1CCc2nnc(NN)cc2C1
Reaction time: 23 h

Procedure:
A suspension of 13.8 g of 6-tert.butyl-3-chloro-5,6,7,8-tetrahydrocinnoline in 100 cc of hydrazine hydrate is stirred in an oil bath of 100° for 23 hours, whereby 20 cc of tetrahydrofuran are added after 1 hour. The mixture is worked up as described in Example 4, and the resulting crude oily title compound is dissolved in 40 cc of absolute ethanol, and hydrochloric acid in ethanol is added to the solution until an acid reaction is obtained. The hydrochloride which crystallizes is triturated with 100 cc of concentrated ammonia, the insoluble title compound is filtered off and has a M.P. of 72°-73° (decomp.).
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](OC=O)(=[O:31])C>ClCCl>[CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([CH:29]=[O:31])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC=O
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10-(4-Cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine of Example 4 (1.065 g) in dichloromethane (50 mL) was reacted with formic acetic anhydride. After stirring at room temperature overnight, the reaction mixture was washed with water and saturated aqueous sodium bicabonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was filtered through a short column of Magnesol® to provide the desired title compound which was used as such in the next step.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(C)ccc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1ccc(Cl)c(C2CC(=O)CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (4.3 g) was added at room temperature diethyl malonate (10.1 g), and then added little by little 4-(2-chloro-5-methylphenyl)-3-buten-2-one (18.9 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (33 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (33 ml) for 15 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(2-chloro-5-methylphenyl)cyclohexane-1,3-dione (7.8 g) as colorless crystals.