Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].O.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3,4-Dihydro-1H-quinolin-2-one (7.2 g, 48.9 mmol) was dissolved in sulfuric acid (150 mL) and cooled to 0° C. Water (35 mL) was added dropwise, followed by nitric acid (3.5 mL, 78 mmol) dropwise following this, retaining temperature below 0° C. The reaction mixture was stirred at 0° C. for 15 min after which LC-MS showed one major peak corresponding to desired product. The reaction mixture was then poured into ice water and extracted with EtOAc (3×); the combined organic phases were dried over MgSO4, filtered and concentrated to afford a brown solid-6-nitro-3,4-Dihydro-1H-quinolin-2-one −8.56 g (91% yield).
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.BrCCCl.[CH:18]1[N:19]=[CH:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]=12>C1COCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:23]2([OH:27])[CH2:24][CH2:25][CH2:26][N:21]3[CH:20]=[N:19][CH:18]=[C:22]23)=[CH:6][CH:5]=1
Reactant: O=C1CCCn2cncc21
Reactant: COc1ccc(CCCBr)cc1
Agent: [Mg]
Solvent: ClCCBr
Solvent: C1CCOC1
Product: COc1ccc(CCCC2(O)CCCn3cncc32)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A three-necked flask with dropping funnel and reflux condenser is charged with 285.000 mmol of magnesium turnings in 50 ml of THF. With stirring at an oil bath temperature of 70° C. a solution of 37.100 mmol of 3-(4-methoxyphenyl)bromopropane [57293-19-3] and 28.500 mmol 1-bromo-2-chloroethane in 40 ml of THF is added dropwise over 45 minutes. The mixture is subsequently stirred at 70° C. for 2 hours and then cooled to room temperature and the supernatant solution is transferred using a transfer cannula into a second three-necked flask, fitted with dropping funnel. The Grignard solution thus obtained is admixed dropwise, with ice-bath cooling, with 28.500 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in solution in 50 ml of THF over 10 minutes. When addition is complete the reaction mixture is stirred at room temperature for 1 hour. It is quenched with 150 ml of 0.5M aqueous HCl and extracted with dichloromethane (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as an amber oil. Rf=0.08 (dichloromethane-ethanol=98:2); Rt=5.50.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=3[N:10]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in methanol (1 ml), a 4N hydrogen chloride-1,4-dioxane solution (1 ml) was added and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was passed through SCX (Bond Elute SCX500MG), the SCX was washed with methanol, and then elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain N2-[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-1H-benzimidazole-2,4-diamine. The compound was identified by LC-MS.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH:7]1([NH:10][NH2:11])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH:7]1([N:10]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:11]2)[CH2:9][CH2:8]1
Reactant: NNC1CC1
Reactant: C/C(N)=C/C#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)n(C2CC2)n1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-amino-2-butenenitrile (903 mg, 11.00 mmol), cyclopropylhydrazine (1194 mg, 11 mmol) and triethylamine (3.07 mL, 22.00 mmol) were suspended in ethanol (100 mL) and heated to 70° C. for 16 hours. The solvent was removed in vacuo. The residue was suspended in 50 mL of saturated NaHCO3 and stirred for 10 minutes. The contents were extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0% to 100% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.13 (m, 4 H), 2.13 (s, 3 H), 3.06 (m, J=6.95, 6.95, 3.79, 3.54 Hz, 1 H), 3.76-3.88 (m, 2 H), 5.24 (s, 1 H). LCMS(ES) [M+H]+ 138.1
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[C:15]([CH3:16])=[C:14]([CH3:17])[NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(#N)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:16][C:15]1[C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])=[CH:3][CH:4]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:13][C:14]=1[CH3:17]
Reactant: Cc1[nH]c2ncnc(Oc3ccc(N)cc3)c2c1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1[nH]c2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2c1C
Reaction time: 1 h

Procedure:
4-(4-Aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine was dissolved in toluene (16 mg) (0.8 ml) and acetonitrile (0.5 ml) under reflux, and then 4-fluorophenyl isocyanate (7.9 μM) was added. The mixture was stirred for 1 hour and returned to room temperature, and then the reaction system was concentrated, diethyl ether was added to the residue, and the resulting crystals were filtered out. The crystals were washed with diethyl ether to obtain the title compound (5 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10](=[O:12])[CH3:11]>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][CH:10]=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC=O
Solvent: CCO
Product: O=CC=Cc1ccc(F)cc1

Procedure:
This compound was prepared following the procedure of Preparation 17 starting from p-fluorobenzaldehyde and acetaldehyde. Yield, 47%. b.p. 80°-95°/2 mm., λmax. (EtOH) 220, 285 nm., ε 10500, 23400.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.[OH-].[Na+]>>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[N:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=1)[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([OH:5])=[O:4])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Clc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc3ccccc3s2)cc1)C(=O)O

Procedure:
Similarly, condensation of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate with 2-chlorobenzothiazole, followed by standard hydrolysis with NaOH afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]3[CH2:21][CH:22]([C:24]4[O:28][N:27]=[C:26]([CH3:29])[N:25]=4)[CH2:23][CH:12]2[CH2:13][C:14]2([CH2:19]3)OCC[O:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:23][CH:22]([C:24]4[O:28][N:27]=[C:26]([CH3:29])[N:25]=4)[CH2:21][CH:20]2[CH2:19][C:14](=[O:15])[CH2:13]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1noc(C2CC3CC4(CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)OCCO4)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1noc(C2CC3CC(=O)CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
9-[(4-Chlorophenyl)sulfonyl]-7-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane] (51) (0.40 g, 0.916 mmol) was covered with HCl in dioxane (4 N, 2 mL). The reaction mixture was stirred at room temperature for 2 h after which it was diluted with EtOAc and washed with aqueous sodium hydroxide (1 N). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to yield 0.36 g (quant.) of 9-[(4-chlorophenyl)sulfonyl]-7-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-one (52). MS (ESI) 396.1 (M+H).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O-])=O)=[CH:22][CH:21]=1.O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:23]4[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(CC(=O)[O-])cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 56.1 %

Procedure:
Sodium spheres (207 mg) were dissolved in ethanol (15 ml) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.0 g) was added, followed by 4-methoxyphenylacetate (1.62 g, 9 mmol) The reaction mixture was refluxed for 16 hours, the solvent was stripped, water was added to the residue, and the product was collected by filtration and recrystallized from ether to afford 0.89 g of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenylmethyl)pyrazolo [3,4-d]pyrimidin-4-one, m.p. 172-173° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:29])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([C:22](O)=[O:23])=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[N:18]2)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]([NH2:55])[CH:49]=1>CN(C=O)C>[NH2:54][C:51]1[CH:52]=[CH:53][C:48]([O:47][CH3:46])=[CH:49][C:50]=1[NH:55][C:22]([C:21]1[N:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][N:8]([CH3:29])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:13]2)[N:18]=[C:19]([C:25]([F:27])([F:28])[F:26])[CH:20]=1)=[O:23]
Reactant: CN(CCN1CCC(n2nc(C(F)(F)F)cc2C(=O)O)CC1)C(=O)OC(C)(C)C
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(N)c(NC(=O)c2cc(C(F)(F)F)nn2C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a stirred solution of 96 (160 mg, 0.381 mmol) in DMF (1.903 mL) was added EDC (88 mg, 0.457 mmol), HOBT (69.9 mg, 0.457 mmol) followed by 4-Methoxy-o-phenylenediamine dihydrochloride (73.1 mg, 0.419 mmol). The mixture was stirred for 16 h at room temperature. After the usual work-up, the residue was purified via Biotage (5% to 15% MeOH/CH2Cl2; 12M column) to afford 106 (172 mg, 84% yield) as yellow oil. LRMS (ESI): calc. 540.6; found 541.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:36][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), decylamine (0.520 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-decyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 73.8% yield).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1>>[Br:1][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[Cl:11]
Reactant: BrBr
Reactant: Fc1cc(Cl)cc(Cl)c1
Product: Fc1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
Bromine (0.6 mol) is added to a mixture of 1,3-dichloro-5-fluorobenzene (0.6 mol) and ferrous powder within 2 hours. The brown reaction mixture is stirred 16 hours at room temperature and subsequently washed with dichloromethane and water. The organic layer is separated, washed with sodium hydrogen carbonate solution and dried with anhydrous sodium sulphate. The solvent is evaporated under reduced pressure. The raw product is recrystallized in ethanol to yield 61 g of the product as a white powder having a melting point of 83° C.
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]([C:8]1[C:13]([C:25]#[C:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Reactant: C#CCCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1ncc(C#CCCc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59; 662 mg, 2.0 mmol), 4-phenyl-1-butyne (260 mg, 2.0 mmol) and triethylamine (0.56 ml, 4.0 mmol) in THF (20 ml) was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (25 mg) and cuprous iodide (12.5 mg) were added and the mixture was stirred for 20 hours. Insoluble material was removed by filtration and washed with diethyl ether (50 ml). The filtrate and washings were combined and concentrated, and the residue was purified by bond elute chromatography, eluting with 25% ethyl acetate in isohexane, to give the product (0.5 g). NMR (CDCl3): 2.85 (m, 2H), 2.95 (m, 2H), 7.05 (m, 2H), 7.1-7.4 (m, 7H), 7.45 (dd, 2H), 8.2 (s, 1H); MS (MH+): 334, 336.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]1[NH:28][CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH2:32][C@H:24]12>>[CH2:23]1[N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH2:32][C@H:24]12
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CCN2CCNC[C@H]2C1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN2CCCC[C@@H]2C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1 436.0)
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:21]3[N:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC3(CC2)OC(=O)Nc2ncccc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
77 mg (0.30 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 88 mg (0.28 mmol) 6-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.17 mL (1.0 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[N:56]1([C:62]2[N:67]=[CH:66][C:65]([NH2:68])=[CH:64][N:63]=2)[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:68][C:65]2[CH:66]=[N:67][C:62]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[N:63][CH:64]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(N2CCOCC2)nc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cnc(N3CCOCC3)nc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.9 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.314 mmol) and stirred for 20 min under argon. 2-MORPHOLIN-4-YLPYRIMIDIN-5-AMINE (23.4 mg, 0.130 mmol, Atlantic Research) was added. After stirred 2.5 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHCO3, water and brine. After dried over Na2SO4, the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(2-morpholinopyrimidin-5-yl)-5-neopentylpyrrolidine-2-carboxamide (78.4 mg., 97.2%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 629.19. found: 629.2.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:2]>C(O)(=O)C.C(O)C.[Pt]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCC#N)[C@H]1c1ccccc1
Agent: [Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1CN[C@H]1CCCN(CCCCN)[C@H]1c1ccccc1
Reaction time: 4 h
Yield: 83.3 %

Procedure:
The title compound of Example 93 (1.9 g) was dissolved in 10 ml of acetic acid in a bottle. To the system was added 1.9 g of 5% platinum/carbon (60% water), and the mixture was shaken under hydrogen (40 p.s.i.) for 4 hours. The mixture was diluted with ethanol, filtered through diatomaceous earth (Celite (trademark)) and the filtrate was concentrated. Saturated aqueous sodium bicarbonate was added to the residue until the pH of the mixture was ca. 8, and the mixture was extracted with chloroform. The chloroform extracts were dried (sodium sulfate) and concentrated to obtain 1.6 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=O)=[CH:6][CH:5]=1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>C1COCC1>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](=[S:16])[NH2:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCN(CC)c1ccc(C(N)=O)cc1
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C(N)=S)cc1
Temperature: 55 °C
Yield: 20.1 %

Procedure:
To a solution of 4-(diethylamino)benzamide (5.66 g, 29.43 mmol) in THF (80 mL) was added P2S5 (9.81 g, 44.14 mmol) at 50° C. over a period of 1 h. The mixture was heated at 55° C. for 8 h, then cooled to rt, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (1.23 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1
Reactant: Cc1nc(-c2ccccc2)nc2sc3c(Cl)nc(Cl)nc3c12
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc2sc3c(N4CCNCC4)nc(Cl)nc3c12
Yield: 43.9 %

Procedure:
3.0 g (8.6 mmol) 2,4-dichloro-9-methyl-7-phenyl-thieno[2,3-d:4,5-d′]dipyrimidine and 2.0 g (23.2 mmol) piperazine are added by stirring to 40 ml tetrahydrofuran at room temperature for 6 h. Thereafter, the solvent is removed, the residue is suspended in water, sucked off, washed with 40 ml water and dried. 1.5 g (44%) 2-chloro-9-methyl-4-piperazin-1-yl-7-phenyl-thieno[2,3-d:4,5-d′]dipyrimidine is obtained.