Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=[O:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH2:52][C@@H:53]([CH:69]([CH3:71])[CH3:70])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=2)[C@H:50]([CH2:72][C@H:73]([C:77](O)=[O:78])[CH:74]([CH3:76])[CH3:75])[O:49][C:48]1([CH3:81])[CH3:80])=[O:46])([CH3:43])([CH3:42])[CH3:41]>CN(C)C=O>[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH2:52][C@@H:53]([CH:69]([CH3:71])[CH3:70])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=2)[C@H:50]([CH2:72][C@H:73]([C:77](=[O:78])[NH:9][C:10]([C:11](=[O:12])[NH2:13])([CH3:15])[CH3:14])[CH:74]([CH3:75])[CH3:76])[O:49][C:48]1([CH3:80])[CH3:81])=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: CC(C)(N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 192 h

Procedure:
106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amide hydrochloride and 91 mg of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) are added in succession to 119 mg of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124c) in 8 ml of dimethylformamide. The reaction mixture is stirred for 8 days at 40° C. The mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by means of FC (60 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.30.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:15])SCC(O)=O)=[CH:5][CH:4]=1.[OH-].[K+].O.[NH2:19][NH2:20].Cl>CO>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:19][NH2:20])=[S:15])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C(=S)SCC(=O)O)cc1
Reactant: NN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=S)NN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step c) (15.0 g) in methanol (200 ml) was added aqueous potassium hydroxide (58.0 ml, 1M) followed by hydrazine monohydrate (3.1 ml) dropwise over 30 minutes. After stirring at room temperature for 1 hour the mixture was acidified to pH 5 with concentrated hydrochloric acid. The resulting precipitate was filtered off and recrystallised from ethanol to afford the sub-title compound (9.9 g) as pale yellow plates. mp 152°-153°.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:27])[N:14]([CH2:15][CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28].CO>>[CH3:27][C:13]1[N:14]([CH2:15][CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:28])[C:11]=2[N:12]=1
Reactant: N
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Temperature: 150 °C

Procedure:
4-Chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline (2.12 g, 5.61 mmol), was combined with an ammonia/methanol solution (7%, 70 mL) in a bomb and heated to 150° C. for 16.5 hours and cooled to ambient temperature. Analysis indicated that the reaction was incomplete. The solution was concentrated under reduced pressure to ˜10 mL, diluted with ammonia/methanol (7%, 50 mL) and reacted in a bomb at 150° C. for 8.5 hours to complete the reaction. The solution was partitioned between dichloromethane and saturated aqueous sodium bicarbonate and the organic layer removed. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane (3×). The organic fractions were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting brown solid was recrystalized from methanol to provide 0.963 g of 2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 111.8-112.5° C.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccc2nc3ccccc3c(N)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc2nc3ccccc3c(N)c2c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a 10 mL rbf equipped with a nitrogen bubbler were charged 3-bromo-9-aminoacridine 5 (120 mg, 0.44 mmol), tert-butyl acrylate (75 μL, 0.48 mmol) and anhydrous DMF (1 mL). Tri-(O-tolyl)phosphine (25 mg, 0.08 mmol) and palladium (II) acetate (6 mg, 0.03 mmol) were added. The reaction mixture was stirred at room temperature and degassed by applying nitrogen flow and vacuum successively (3 times). The mixture was finally placed under nitrogen atmosphere and triethylamine (185 μL, 1.32 mmol) was added. The red-orange solution was heated to 110° C. for 3 hours and then cooled to room temperature. The brown-orange solution was filtered through Celite and washed with ethyl acetate. This organic layer was then washed with water and concentrated in vacuo to give the crude product as an orange oil. Purification by Flashmaster II using a gradient elution (DCM→DCM:MeOH 60:40) afforded pure 3-(9-amino-acridin-2-yl)-acrylic acid tert-butyl ester 6 as an orange solid (75 mg, 53%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20](CC3OC(CO)=CC=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[O:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.[CH2:40](OCC)[CH3:41]>>[OH:33][CH2:38][C:37]1[O:36][C:35]([CH2:34][CH:9]2[CH2:10][CH:11]([C:14]([C:16]3[NH:17][C:18]4[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=4[N:20]=3)=[O:15])[CH2:12][CH2:13][NH:8]2)=[CH:41][CH:40]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: O=C(c1nc2ccccc2[nH]1)C1CCNC(Cc2ccc(CO)o2)C1
Reaction time: 0.75 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (5 mmol) and dioxane (25 mL). Slowly add a solution of hydrochloric acid in dioxane (1.25 mL, 4 M, 5 mmol). After 45 minutes, add diethyl ether and evaporate in vacuo to give a residue. Partition the residue between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:11][C:12]1[N:17]=[C:16]([NH:8][C:5]2[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Nc1cc(C(F)(F)F)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-(trifluoromethyl)-1H-pyrazol-3-amine (500 mg, 3.3 mmol), 2,4,5-trichloropyrimidine (607 mg, 3.3 mmol) and sodium carbonate (525 mg, 5 mmol) in anhydrous EtOH (10 mL) was stirred at rt. After one day, LCMS showed the reaction was not complete. Additional 2,4,5-trichloropyrimidine (0.15 mL) and sodium carbonate (525 mg) were added and the reaction continued for two more days. The solvent was evaporated, and the residue was extracted with DCM (3×20 mL). The combined DCM layers were washed with brine (10 mL), dried over Na2SO4 and evaporated. The crude product was purified by silica chromatography (0-50% EtOAc in hexanes gradient) to give 2,5-Dichloro-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine as a light tan colored solid; ESMS m/z 297.9 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:5]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1.Br[C:32]1[C:33](C2C=CN=CC=2)=[C:34]([C:47]2[CH:52]=[CH:51][C:50](F)=CC=2)[N:35]([Si](C(C)C)(C(C)C)C(C)C)[CH:36]=1.C1C2N(CCC(=O)C2)CC1.C(N1CCC(=O)CC1)C1C=CC=CC=1>>[F:24][C:19]1[CH:18]=[C:17]([C:4]2[NH:5][CH:6]=[C:2]([C:52]3[CH2:47][CH:34]4[N:35]([CH2:36][CH2:32][CH2:33]4)[CH2:50][CH:51]=3)[C:3]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)c(F)c1
Agent: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C1CCN2CCCC2C1
Product: Fc1ccc(-c2[nH]cc(C3=CCN4CCCC4C3)c2-c2ccncc2)cc1F

Procedure:
In a similar manner to the procedures described in Examples 9(i) and 9(iii) above, coupling, dehydration and desilylation reactions were carried out using 4-bromo-2-(3,4-difluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole (prepared as described in Preparative Example 5 below), instead of 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole, and (±)-1,2,3,5,6,7,8,8a-octahydroindolizine-7-one, instead of 1-benzylpiperidine-4-one, as starting materials to afford a mixture of the title compound and the (1,2,3,5,6,8a-hexahydroindolizin-7-yl) isomer thereof (which is the compound of Example 92 below). The mixture was separated by chromatography on a silica gel column using a 100:10:1 by volume mixture of ethyl acetate, methanol and isopropylamine as the eluant to give the title compound (yield 29%, Rf value=0.66) as a pale pink powder.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2)(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: Cl
Product: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 85 °C
Yield: 97.2 %

Procedure:
A mixture of 259 mg (1.16 mmol) of 5-acetamido-6-nitroindan in 4 mL of 2N HCl was heated at 85° C. for 9 h and cooled to room temperature. The solid precipitate was filtered, washed with water, and dried to leave 201 mg (97%) of a crystalline yellow solid. 1H NMR (CDCl3), 2.068 (m, 2), 2.843 (m, 4), 6.00 (sb, 2), 6.650 (s, 1), 7.942 (s, 1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][SH:3].Cl.[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:3][CH2:2][CH2:1][NH2:4])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Agent: Cl
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
For protecting thiol groups, take 2-thioethylamine hydrochloride and triphenylmethanol as reactants and boron trifluoride-diethyl ether complex is used as a catalyst to get 2-[(triphenylmethyl)thio]ethylamine. The reaction temperature is 72 degrees Celsius and the reaction time is 4 hours. Step (2): Use 2-[(Triphenylmethyl)thio]ethylamine and chloroacetyl chloride to carry out the amidation reaction in trichloromethane solution so as to produce N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide. Step (3): Take 2-[(Triphenylmethyl)thio]ethylamine, N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide and use triethylamine used as a reagent to carry out the substitution reaction in dichloromethane solution. Thus an amine-amide-thiol ligand is produced. The reaction temperature of the substitution reaction is 55° C. and the reaction time is 48 hours. Step (4): Dissolve 6-bromohexanoic acid and thionyl chloride in absolute methanol solution to carry out the esterification reaction and get methyl 6-bromohexanoate. The reaction temperature of the esterification reaction is 25° C. and the reaction time is 24 hours. Step (5): Take the amine-amide-thiol ligand and methyl 6-bromohexanoate and use sodium hydroxide (NaOH) as a reagent to carry out the substitution reaction in acetonitrile solution and get methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate. The reaction temperature of the substitution reaction is 85° C. and the reaction time is 24 hours. Step (6): Hydrolyze methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate in alkaline methanol solution to get 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenyl-methyl)thio]dodecanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[NH:10][C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6].[CH2:27]([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH3:27])[C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Yield: 78 %

Procedure:
(3R)-4-(2,4-Dimethoxybenzoyl)-3-ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one (see Example 18) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-4-(2,4-dimethoxybenzoyl)-3-ethyl-6-fluoro-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (78%).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][C:10]([F:17])([F:16])[S:11]([O:14]C)(=[O:13])=[O:12]>>[F:9][C:10]([F:17])([F:16])[S:11]([O-:14])(=[O:13])=[O:12].[CH3:10][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: COS(=O)(=O)C(F)(F)F
Product: C[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 26 %

Procedure:
Trichloroisothiazole (9.4 g, 0.05 mol) and 9 ml of methyl trifluoromethane sulfonate were heated at 65° for 30 min. After cooling, either (150 ml) was added and the solid collected to yield 4.6 g (26%) of product, mp 118-120. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([B:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])(C)(C)C.Cl.[CH3:38][O:39][C:40]([NH:42][CH:43]([CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)C(O)=O)=[O:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:38][O:39][C:40](=[O:41])[NH:42][CH:43]([CH:47]1[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)[C:6](=[O:7])[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([B:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:35])([CH3:36])[O:29]4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C1CCOCC1
Temperature: 25 °C

Procedure:
2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.717 mmol) was dissolved in DCM (8 mL) at room temperature. HCl (4N in dioxane, 8 mL) was added and stirring at room temperature was continued. After all starting material was consumed, the volatiles were removed in vacuo and the crude material was dissolved in DMF. Methoxy carbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (155 mg, 0.715 mmol), DIEA (276.6 mg, 2.1 mmol), and HATU (272 mg, 0.715 mmol) were added. After all starting material was consumed, the reaction was diluted with EtOAc and was washed with brine/aqueous bicarbonate. The organic layer was dried over sodium sulfate. Filtration and evaporation of solvents in vacuo gave the crude product, which was purified via flash chromatography on silica gel (eluent: EtOAc/hexanes) to yield 355 mg.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12
Product: FC(F)(F)c1cccc(-c2cc(Cl)n3nccc3n2)c1

Procedure:
A mixture of 1.75 g. of 7-hydroxy-5-(α,α,α-trifluoro-m-tolyl) pyrazolo[1,5-a]pyrimidine and 15 ml. of phosphorus oxychloride is refluxed for 2 hours. After evaporation at reduced pressure, ice is added to the residue and the desired compound is extracted with methylene chloride. After washing the organic layer with a saturated saline solution and drying with solid anhydrous sodium sulfate, evaporation gives the desired compound, m.p. 137°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([O:19]CC)=[O:18])[C:14]([N+:22]([O-:24])=[O:23])=[C:13]([NH:25][C:26]3[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]([N+:22]([O-:24])=[O:23])=[C:13]([NH:25][C:26]3[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1nc(N[C@@H](C)c2ncc(F)cn2)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(C(=O)O)c2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of ethyl 2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidine-4-carboxylate (Intermediate 49, 2 mmol) in THF/MeOH (1:1 v/v, 10 ml) was added LiOH (0.42 g) in H2O (1 ml) and the resulting mixture was stirred at ambient temperature overnight. The volatiles were evaporated under reduced pressure and the solid left was diluted with H2O. The aqueous layer was acidified with 1N HCl (aq) solution and extracted with EtOAc (3×). The combined organic layers were dried and evaporation gave the title compound (406 mg), used in the next step without further purification. LCMS: 402 [M−1].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.O>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 90 %

Procedure:
As described in Example VI, a mixture of 5.6 g. of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydropyrido(2,3-d)pyrimidine, 7.04 g. of N-benzylpiperazine and 80 cm3 of toluene is heated under reflux for 2 hours. After cooling, the mass is diluted with 100 cm3 of chloroform and is taken up in 200 cm3 of water. After washing the organic phase with water, the reaction product is isolated as described in the Example mentioned. It is recrystallised from isopropanol. 7.6 g. (90%) of 2-(4'-benzyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine are obtained; melting point 152° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:19])[C:9]=1[O:10][CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:5]#[N:6].[ClH:20].[NH2:21][OH:22].C([O-])(O)=O.[Na+]>CO.CC(=O)OCC>[Cl:20][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:19])[C:9]=1[O:10][CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:5](=[NH:6])[NH:21][OH:22]
Reactant: CCOC(COc1c(C)cc(C#N)cc1Cl)OCC
Reactant: Cl
Reactant: NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(COc1c(C)cc(C(=N)NO)cc1Cl)OCC
Temperature: 75 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 3-chloro-4-(2,2-diethoxyethoxy)-5-methylbenzonitrile (4.54 g, 16.0 mmol) in methanol (50 mL), hydroxylamine hydrochloride (3.34 g, 48.0 mmol) and NaHCO3 (2.69 g, 32.0 mmol) is added. The mixture is stirred at 75° C. for 2 h before it is diluted with EA (120 mL) and washed with water (100 mL). The washing is extracted twice with EA (2×75 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated to give the title compound (4.43 g) as a beige wax which slowly solidifies upon standing; LC-MS: tR=0.55 min, [M+1]+=317.28.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:5]2=[C:4]([C:19](O)=[O:20])[N:3]=1.[CH3:22][NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:11][C:5]2=[C:4]([C:19](=[O:20])[NH:26][C@@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]([NH:23][CH3:22])=[O:31])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(Br)nc(C(=O)O)c2C1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CCC2
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 3-bromo-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxylic acid (33E) (1.08 g, 3.0 mmol), H-Leu-NHMe (20B) (0.62 g, 4.30 mmol) and DIEA (0.52 mL, 3.0 mmol) in DMF (25 mL) was added TBTU (1.46 g, 4.55 mmol) in two batches over 10 min at 0° C. After stirring from 0° C. to room temperature overnight, the reaction was quenched with water and evaporated under vacuum. The residue was extracted between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography with 60% to 100% EtOAc/Hex to give an oily product 55A at 51% yield. LCMS (+ESI) m/z 486.1, 489.1 [M+H]+.