Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][C:20](=[O:23])[N:19]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O.O>CO.C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][C:20](=[O:23])[N:19]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCCCCCN1C(=O)CCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Li]O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCCCCCCN1C(=O)CCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.5 %

Procedure:
A mixture of methyl 2- (4,5-diphenyl-2-oxazolyl)-5-oxo-l-pyrrolidineoctanoate (3.60 g, 7.8 mmol) , LiOH.H2O (986 mg, 24 mmol), MeOH (60 mL) and H2O (10 mL) was stirred at room temperature. After about 45 minutes, the mixture was concentrated, diluted with 1N HCl solution and extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and concentrated to leave an oil. Chromatography on a column of silica gel using a mixture of MeOH and CHCl3 (1:1) as eluent furnished 2-(4,5-diphenyl-2-oxazolyl) -5-oxo-1-pyrrolidineoctanoic acid (1.76 g, 50%). IR (Film) 3600-2400 (CO2H), 1725 (CO2H), 1695 (N.CO) cm-1 ; 1H NMR (CDCl3) δ1.20-1.65 (10H, m, CH2), 2.24 (2H, t, J=7.5 Hz, CH2CO2H), 2.30- 2.60 (3H, m, CH2 of ring), 2.75 (1H, m, CH2 of ring), 3.03 (1H, m, NCH2 of side chain), 3.60 (1H, quintuplet, J=7 Hz, NCH2 of side chain), 4.90 (1H, m, NCH of ring), 5.26 (0.3H, s, CH2Cl2), 7.30-7.45 (6H, m, aromatic H), 7.50-7.65 (4H, m, aromatic H), 9.87 (1H, bs, CO2H); MS m/z 447 (MH+).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C-:22]#[N:23].[Na+]>CN(C)C=O>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:22]#[N:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CC#N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
38.2 g of crude trans-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexylmethyl ester and 16.7 g (340 mmol) of sodium cyanide dissolved in 380 ml of N,N-dimethylformamide were stirred for 2 hours at 80° C. After cooling the reaction mixture down to room temperature, it was partitioned between ether and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 9:1 v/v mixture of hexane and ethylacetate as the eluent giving 24.2 g (79.7% over two steps) of pure trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-acetonitrile as colorless viscous oil, MS: 290 (MNa+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([OH:13])=[O:12].[CH3:14][CH2:15]O>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCO
Reactant: O=C(O)CC1Cc2ccccc2C1
Product: CCOC(=O)CC1Cc2ccccc2C1
Yield: 90 %

Procedure:
A solution of acid 147 (32.0 g, 180 mmol) in dry EtOH (250 mL) and CH2SO4 (2.0 mL) was stirred at reflux temperature under N2 for 16 h. The solvent was evaporated, the residue partitioned between ice/water (200 mL) and DCM (50 mL) and the aqueous layer extracted with DCM (2×40 mL). The combined organic layer was washed with saturated aqueous NaHCO3 solution and water, dried and the solvent evaporated to yield ester 148 (33.3 g, 90%) (lit. Tanaka, et. al., J. Med. Chem. 1994, 37, 2071-2078) as a brown oil: 1H NMR δ 7.10-7.21 (m, 4H, H-4, H-5, H-6, H-7), 4.15 (q, J=7.1 Hz, 2H, CH2), 3.10-3.45 (m, 2H, H-1, H-3), 2.82-2.94 (m, 1H, H-2), 2.62-2.68 (m, 2H, H-1, H-3), 4.48 (d, J=7.4 Hz, 2H, CH2CO2), 1.27 (t, J=7.1 Hz, 2H, CH3).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[N:13]=[CH:12]2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.Cl.[NH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([C:14]2[N:13]=[CH:12][N:11]([C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=[C:2]([C:29]4[CH:30]=[C:25]([NH2:24])[CH:26]=[CH:27][CH:28]=4)[N:3]=3)[CH:15]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2cn(-c3nc(Br)cn4ccnc34)cn2)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cn(-c3nc(-c4cccc(N)c4)cn4ccnc34)cn2)cc1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A mixture of 6-bromo-8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazine (4) (870 mg), 3-aminophenylboronic acid hydrochloride (511 mg), tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) (142 mg), 1 M aqueous sodium carbonate (Na2CO3) (7.4ml), and 1,2-dimethoxyethane (DME) (35 ml) is heated at 90 ° C. for 16 hours. The mixture is cooled to rt, treated with water (50 ml) and extracted with ethyl acetate (3×80 ml). The extracts are washed with water (1×50 ml) and brine (1×50 ml), dried over MgSO4, and evaporated in vacuo to give a semi-solid which is triturated with diethyl ether/methanol (10:1) to give 3-[8-(4-p-Tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (600 mg) as a cream-colored solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH3:29][O:30][C:31](=[O:58])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:57])[NH:39][CH:40]([C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)[C:41]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=O>C(Cl)Cl.C(OCC)(=O)C.O>[CH3:29][O:30][C:31](=[O:58])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[O:57][C:41]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[C:40]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[N:39]=1
Reactant: COC(=O)CCCCCCC(=O)NC(C(=O)c1ccc(OC)cc1)c1ccncc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCc1nc(-c2ccncc2)c(-c2ccc(OC)cc2)o1
Reaction time: 0.5 h

Procedure:
Triphenyl phosphine (278 mg, 1.06 mmol), iodine (269 mg, 1.06 mmol) and triethylamine (0.3 mL, 2.12 mmol) were added at 0° C. to a solution in which 7-[2-(4-methoxy-phenyl)-2-oxo-1-pyridin-4-yl-ethylcarbamoyl]-heptanoic acid methyl ester (218 mg, 0.53 mmol) prepared in Step 5 was dissolved in 1.5 mL of methylene chloride, and the resulting mixture was stirred for 30 min. The reaction materials were elevated to room temperature and were further stirred for 1 day. After the reaction was complete, the reaction materials were diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography to afford 7-[5-(4-methoxy-phenyl)-4-pyridin-4-yl-oxazol-2-yl)-heptanoic acid methyl ester of the following formula.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:60][CH3:61].C(OCC)(=O)C>CN(C)C=O>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH2:60][CH3:61])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(O)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cc(C(C)C)ccc2OC)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-hydroxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (70 mg) is dissolved in N,N-dimethylformamide (3 ml) and thereto are added potassium carbonate (26.4 mg) and iodoethane (29.8 mg) and the mixture is stirred at 50° C. for 8 hours. Thereto are added ethyl acetate and a water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-ethoxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (60.5 mg). MS (m/z): 762 [M+H]+
Reaction SMILES: [CH3:1][C@@:2]1([OH:41])[C@H:6]([O:7]CC2C=CC(Cl)=CC=2Cl)[C@@H:5]([CH2:17][O:18]CC2C=CC(Cl)=CC=2Cl)[O:4][C@H:3]1[N:28]1[CH:40]=[C:32]2[CH2:33][CH2:34][C:35]3[CH2:36][NH:37][N:38]=[CH:39][C:30]([C:31]=32)=[N:29]1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][C@@:2]1([OH:41])[C@H:6]([OH:7])[C@@H:5]([CH2:17][OH:18])[O:4][C@H:3]1[N:28]1[CH:40]=[C:32]2[CH2:33][CH2:34][C:35]3[CH2:36][NH:37][N:38]=[CH:39][C:30]([C:31]=32)=[N:29]1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1N1C=C2CCC3=C2C(=N1)C=NNC3
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=C2CCC3=C2C(=N1)C=NNC3
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of compound 4.5 (68.0 mg, 0.1 mmol) in CH2Cl2 (10 mL) at −78° C. was added 1.0 M solution of BCl3 in CH2Cl2 (1.07 mmol) dropwise via syringe. The mixture was stirred at −78° C. for 1.5 h, then for 3 hr at −35° C. to −40° C. The reaction was quenched by adding MeOH (6.0 mL), the solvents were evaporated and the resulting residue was purified by flash column chromatography over silica gel using 6-7% MeOH in CH2Cl2 as eluent to give title compound 4.6 (31.8 mg) as a white foam.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C2CC2)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C2CC2)c1
Yield: 56.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (170 mg) described in Preparation Example 144 and oxazolidin-2-one (55 mg), the title compound (97 mg) was obtained.
Reaction SMILES: [Br:1]C(C)(CBr)C(OC(N(F)F)CN(F)F)=O.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[Br-:1].[Br-:1].[C:30]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(Br)(CBr)C(=O)OC(CN(F)F)N(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: [Br-]

Procedure:
Employing a system similar to that used in Example I, 20.8 parts (0.055 mole) 1,2-bis(difluoramino)ethyl α,β-dibromoisobutyrate is added over a period of thirty minutes to 14.45 parts (0.055 mole) triphenylphosphine in 200 ml. of anhydrous diethyl ether to give an immediate precipitate of triphenylphosphine dibromide. Another 100 ml. of anhydrous ether is added during the course of the addition to facilitate stirring of the mixture. After 18 hours the mixture is filtered free of solids followed by removal of the ether at reduced pressure on a rotary evaporator. The residue when examined by gas chromatography is found to be 97-98 percent pure. Distillation of the residue gives 7.5 parts (63 percent) of 1,2-bis(difluoramino)ethyl methacrylate (b.p. 50° C/5.5 mm. of mercury), nD20 1.3944. Identification is based on infrared spectral data and elemental analysis. The product conforms to the known 1,2-bis(difluoramino)-ethyl methacrylate. The product gives the following analysis:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=1)[CH2:16]2
Reactant: Nc1ccccc1
Reactant: Ic1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Product: c1ccc(Nc2ccc(-c3ccc(OC4CN5CCC4CC5)cc3)cc2)cc1

Procedure:
The product of Example 8A (405 mg, 1 mmol) was treated with aniline (110 mg, 1.2 mmol) according to the procedure in Example 8B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.25) as solid (200 mg, yield, 54%). 1H NMR (MeOH-d4, 300 MHz) δ 1.42-1.56 (m, 1H), 1.62-1.88 (m, 2H), 1.99-2.12 (m, 1H), 2.14-2.22 (m, 1H), 2.73-3.02 (m, 5H), 3.27-3.38 (m, 1H), 4.51-4.59 (m, 1H), 6.80-6.87 (m, 1H), 6.94 (d, J=8.8 Hz, 2H), 7.06-7.15 (m, 4H), 7.18-7.26 (m, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 371 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([O:17]CC)=[O:16])[C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3].[OH-].[Na+]>C1COCC1.C(O)C.O>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([OH:17])=[O:16])[C@H:9]([C:11]([F:13])([F:14])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H](C(=O)OCC)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N[C@H](C(=O)O)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.50 g (22.9 mmol) of ethyl (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovalinate (diastereomer mixture) were dissolved in a mixture of in each case 28 ml of THF, ethanol and water, and 13.77 g (344 mmol) of sodium hydroxide were added at 0° C. Ice-cooling was removed and the reaction mixture was stirred at RT overnight. The mixture was then added to water, acidified with semiconcentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 4.39 g of the target product which was not purified any further (75% of theory, diastereomer ratio about 2.5:1).
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH2:66][CH:67]3[CH2:69][CH2:68]3)[C:64](=[O:65])[C:39]=12)C1C=CC=CC=1>>[CH:67]1([CH2:66][N:63]2[CH2:62][CH2:61][N:40]3[C:41]([CH2:45][C:46]4([C:51]5[C:60]6[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=6)[CH:54]=[CH:53][CH:52]=5)[CH2:47][CH2:48][CH2:49][CH2:50]4)=[N:42][C:43](=[O:44])[C:38]([OH:37])=[C:39]3[C:64]2=[O:65])[CH2:69][CH2:68]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1CC1CC1
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: O=C1c2c(O)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1CC1CC1

Procedure:
This compound was prepared by following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 9-benzyloxy-2-cyclopropylmethyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (360) (100 mg, 0.19 mmol). The yield was 42 mg, 51%, of a white solid.
Reaction SMILES: [CH2:1]([N:21]=[C:22]=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH3:24]>C1(C)C=CC=CC=1>[CH2:1]([NH:21][C:22]([NH2:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCNC(N)=O
Reaction time: 0.5 h

Procedure:
80.75 g (0.25 mole) of eicosylisocyanate are dissolved in 350 ml of technical-grade toluene and, at a temperature of 50°-60° C., 4.25 g (0.25 mole) of liquid NH3 are slowly added, in a pressure vessel, with stirring. After an after-stirring period of 30 minutes, the N-eicosyl-urea is isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]2[CH2:30][O:29]2)[N:11]=1.C1COCC1.[CH3:36][NH:37][CH3:38]>C(O)C>[CH3:36][N:37]([CH3:38])[CH2:30][CH:28]([OH:29])[CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[N:11]1
Reactant: CNC
Reactant: Cc1cccc(C)c1Nc1nn(CCC2CO2)c2nc(Nc3ccccc3)ncc12
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C)c1Nc1nn(CCC(O)CN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 60 mg (0.15 mmol) of N3-(2,6-dimethylphenyl)-1-(2-(oxiran-2-yl)ethyl)-N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 42 (Example 9, Step A) in 4 mL of absolute ethanol was treated with 375 μl (2.0 M, 0.8 mmol) of a THF solution of dimethylamine. The resulting yellow solution was stirred at room temperature for 2.5 h and then heated to 40° C. for an additional 2 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 19:1 grading to CH2Cl2:MeOH, 9:1) to give the title compound 43. 1H-NMR (CD3OD) δ 1.75-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.19 (s, 6H), 2.26 (s, 6H), 2.27-2.43 (m, 2H), 3.63-3.70 (m, 1H), 4.17-4.31 (m, 2H), 7.00 (t, J=7.4 Hz, 1H), 7.09-7.16 (m, 3H), 7.30 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.7 Hz, 1.0 Hz, 2H), 8.10 (s, 1H). Mass Spectrum (ESI) m/e=446.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH2:21][C:22]([NH:1][C@H:2]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:3][OH:4])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: N[C@@H](CO)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H](CO)c1cc(F)cc(F)c1
Reaction time: 0.33 h

Procedure:
To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol from Step B (630 mg, 3.64 mmol) and triethylamine (0.51 mL, 3.64 mmol) in CH2Cl2 (40 mL) at 0° C. was added chloroacetyl chloride (0.29 mL, 3.64 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[F:30][C:31]([F:37])([F:36])[O:32][CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[F:30][C:31]([F:37])([F:36])[O:32][CH2:33][CH2:34][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: NCCOC(F)(F)F
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOC(F)(F)F)ccc21
Yield: 68.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-trifluoromethoxy-ethyl)-amide (87 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-(trifluoromethoxy)ethylamine hydrochloride (45 mg), HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 520.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.41 (bs, 1H), 8.72 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.23 (t, 2H), 3.81-3.55 (m, 5H).
Reaction SMILES: C[O:2]/[CH:3]=[CH:4]/[CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:7]=2[O:6]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(Cl)Cl>[O:2]=[CH:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:7]=2[O:6]1
Reactant: CO/C=C/C1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(-c2ccc3c(c2)CC(CC=O)O3)cc1
Yield: 86.5 %

Procedure:
A solution of Example 67A (0.5 g, 1.8 mmol) in acetone (10 mL) and p-toluenesulfonic acid monohydrate (0.51 g, 2.7 mmol) was stirred for 45 minutes, diluted with CH2Cl2 (150 mL), washed with cold aqueous sodium bicarbonate (2×100 mL, 10% solution), water (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2Cl2 to give the titled compound (0.41 g, 87%). 1HNMR (CDCl3): 2.95 (m, 2H), 3.65 (m, 3H), 6.82 (d, J=7 Hz, 1H), 7.40 (m, 2H), 7.62 (m, 4H), 9.55 (d, J=7 Hz, 1H); MS (DCI) 263 (M+), 281 (M+NH4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:25])[CH2:8][CH:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+:27]>O>[Na+:27].[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:25])[CH2:8][CH:9]2[CH2:12][C:13]([O-:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CC(=O)O)CC2=C1C(=O)Nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)C(CC(=O)[O-])CC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A suspension of 8 g [6-methoxy-3-(2-oxo-1,2-dihydroindol-3-ylidene)indan-1-yl]-acetic acid in 60 ml of water was added to 0.9 g of sodium hydroxide in 10 ml of water. The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was frozen and lyophilized to give 8 g of [6-methoxy-3-(2-oxo-1,2-dihydroindol-3-ylidene)-indan-1-yl]-acetic acid sodium salt.