Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](Cl)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:27]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH:27]1([CH2:31][NH:32][C:24]([C:21]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:8]([CH3:9])[CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[C:23]=3[CH:22]=2)=[O:25])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Reactant: NCC1CCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CCC3)cc21
Yield: 48.6 %

Procedure:
By working in a manner similar to that described below in Example 103, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (3.4 g) in dichloromethane (100 cc) and with cyclobutylmethylamine (4.5 g), N-(cyclobutylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.7 g) is obtained, after recrystallization in isopropyl ether, in the form of white crystals, m.p. 133° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:30])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH2:27][C:28]#[N:29])[CH:24]=[CH:23][CH:22]=1.C([O:33][CH:34]=[C:35]([C:41](OCC)=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])C>O1CCCC1.C(O)(=O)C>[C:28]([C:27]1[CH:41]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:34](=[O:33])[N:26]2[C:25]=1[CH:24]=[CH:23][CH:22]=[C:21]2[C:14]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:30])#[N:29]
Reactant: Cc1cc(C)c(-c2cccc(CC#N)n2)c(C)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cc(C#N)c2cccc(-c3c(C)cc(C)cc3C)n2c1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Diisopropylamine (1.6 mL, 11.6 mmol) in tetrahydrofuran (15 mL) was charged with n-butyllithium (2.5M, 4.6 mL, 11.6 mmol) at 0° C. The reaction stirred for 0.5 h. The solution was cooled to −20° C. and (6-mesitylpyridin-2-yl)acetonitrile (2.49 g, 10.5 mmol) was added drop wise (as a solution in 5 mL tetrahydrofuran). After 0.5 h, the solution was cooled to −78° C. and diethyl ethoxymethylenemalonate (2.1 mL, 10.5 mmol) was added. The reaction stirred for 0.5 h and was then cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an orange residue. The material was dissolved in acetic acid (20 mL) and heated at 100° C. for 4 h. The solution was cooled and poured into an Erlenmeyer flask and washed with water. The solution was neutralized with saturated sodium bicarbonate. The solution was extracted with ethyl acetate (3 times), dried, and concentrated. Flash chromatography (25% ethyl acetate/hexanes) gave 3.19 g (84% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8](Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>O.C(O)C(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: O
Product: CCCCCCCCCCN1CCN(C)CC1
Temperature: 150 °C
Yield: 74.9 %

Procedure:
100 g (1 mole) of 1-methyl-piperazine and 176.5 g (1 mole) of decyl chloride were heated under reflux, at an external temperature of 150° C, until the reaction mixture had ceased boiling. After cooling, the solid product was extracted by shaking with a mixture with 40 g (1 mole) of sodium hydroxide in 500 ml of water and 500 ml of isobutanol. The organic phase was separated off and concentrated, and the residue was extracted with petroleum ether. After evaporating the petroleum ether solution, 180 g (75% of theory) of 1-methyl-4-decyl-piperazine were obtained in a form which was pure according to thin layer chromatography.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.F[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=1[F:32].[C:33](=O)([O-:35])[O-:34].[K+].[K+]>C1COCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:17]2[N:18]=[CH:19][C:20]([I:23])=[CH:21][C:22]=2[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[F:32]
Reactant: Fc1ccc(I)cn1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=C([O-])[O-]
Agent: CC1(C)CCCC(C)(C)N1
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(I)cnc1Oc1ccc(Br)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A solution of n-butyllithium (150 mL, 375 mmol) in 950 mL THF was cooled to −10° C. and treated with a solution of 2,2,6,6-tetramethylpiperidine (72.7 mL, 428 mmol) in 50 mL THF. After stirring for 15 min, the solution was cooled to −78° C. and 2-fluoro-5-iodopyridine (80 g, 357 mmol) was added as a solution in 400 mL THF dropwise via addition funnel over 60 minutes. After stirring for an additional 30 min, CO2 was bubbled through the red solution for 10 minutes. The cooling bath was removed, and CO2 was bubbled through the reaction mixture for an additional hour. The reaction mixture was concentrated in vacuo, triturated with hexanes and again concentrated in vacuo. The crude residue was taken up in 360 mL DMF and was treated with 4-bromo-3-fluorophenol (68.1 g, 357 mmol) followed by potassium carbonate (61.6 g, 446 mmol). The resulting mixture was heated to 120° C. for 18 h. The reaction mixture was cooled to rt and filtered through celite. The filtrate was diluted with EtOAc (500 mL) and was acidified to pH 3 with 6 N HCl. The organics were washed with water, brine, dried over MgSO4 and concentrated in vacuo. The crude residue was triturated with ether/hexanes, and the derived solid was dried under a stream of nitrogen to provide 2-(4-bromo-3-fluorophenoxy)-5-iodonicotinic acid (108.93 g, 249 mmol) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([F:34])[CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:57][CH2:58][C:59]([CH3:68])([CH3:67])[CH2:60][NH:61][C:62](=[O:66])[C:63]([NH2:65])=[O:64].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:57][CH2:58][C:59]([CH3:68])([CH3:67])[CH2:60][NH:61][C:62](=[O:66])[C:63]([NH2:65])=[O:64])=[O:30])=[C:27]([F:34])[CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CNC(=O)C(N)=O
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1F
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: CC(C)(CNC(=O)C(N)=O)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzoic acid (10 mg) and TBTU (7.74 mg) in DMF (1 mL) was added N1-(3-amino-2,2-dimethylpropyl)oxalamide (4.18 mg) and DIPEA (0.018 mL). The mixture was stirred at room temperature for 2 hours. The product was isolated by using preparative HPLC system.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:10]([F:13])([F:12])[F:11])=[N:17][N:16]=[N:15]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nnnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Three grams (12.4 mmol) of N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 11, 1.46 g (22.3 mmol) of sodium azide, 0.85 g (6.20 mmol) of triethylamine hydrochloride, and 30 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 24.5 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (20 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 2.84 g of 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 92.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[F:13][C:14]([F:19])([F:18])C([O-])=O.[K+]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[C:14]([F:19])([F:18])[F:13]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Product: COc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similat to that of Procedures 3 and 4.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)=[O:2].C1(C)C=CC(S(O)(=O)=[O:28])=CC=1.[C:32]1([CH3:38])C=CC=CC=1>CO.C(O)CO>[O:2]1[CH2:38][CH2:32][O:28][CH:1]1[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Solvent: CO
Solvent: OCCO
Product: O=C(Nc1ccccc1)c1cn2cc(C3OCCO3)ccc2n1

Procedure:
To a solution of 137 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 8) in 5 mL of toluene are added 45 μL of ethylene glycol, 169 mg of para-toluenesulfonic acid and molecular sieves. The mixture is refluxed for 24 hours in a round-bottomed flask equipped with Dean-Stark apparatus, and then cooled, filtered, diluted with 100 mL of dichloromethane and washed with 2N sodium hydroxide and with water. The organic phases are dried and concentrated to dryness to give a mixture of the starting material and of the expected product, which is redissolved in 5 mL of methanol containing 410 μL of ethylene glycol, 130 mg of para-toluenesulfonic acid and molecular sieves. The mixture is heated for 16 hours at reflux and then cooled, filtered and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a 70/30 mixture of dichloromethane and ethyl acetate to give 53 mg of 6-(1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Na+].[Cl-]>CN1CCCC1=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 120 °C
Yield: 92.3 %

Procedure:
A homogeneous mixture of 4-fluoro-3-methylnitrobenzene 1 (20 g, 129 mmol) and N-methylpiperazine 3 (25.82 g, 258 mmol) in N-methylpyrrolidone (NMP) (10 mL) was refluxed (120° C.) under N2 for 24 hours. The reaction mixture upon cooling to room temperature was poured over a saturated NaCl solution (100 mL). The resulting solid was sonicated for approx. 30 seconds, filtered, washed with ice-cold water (2×10 mL) and dried under high vacuum to obtain 4-(4-methylpiperazin-1-yl)-3-methylnitrobenzene 5 (28 g, 92%). 1H NMR (CD3OD): δ 8.02 (m, 2H), 7.13 (d, 1H, J=9.3 Hz), 3.08 (m, 4H), 2.66 (m, 4H), 2.38 (s, 6H); LCMS: purity: 99%, MS (m/e): 236 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([OH:8])=O.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30]([N:33]1[CH2:34][CH2:35][N:36]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:37][CH2:38]1)(=[O:31])=[O:32])[CH:24]=[CH:23]2
Reactant: COc1cc(C(=O)O)ccc1-c1ccncc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)ccc1-c1ccncc1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 3-methoxy-4-(4-pyridyl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]([O:17][C@H:18]([CH3:45])[C@H:19]([NH:22][C:23]1[CH:28]=[C:27]([F:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:37]=2)[CH3:32])[N:24]=1)CO)([CH3:16])([CH3:15])[CH3:14].N1C(C)=CC=CC=1C>C(Cl)Cl.[Cl-].[Na+]>[C:13]([O:17][C@@H:18]([C@H:19]1[CH2:7][O:6][C:5](=[O:11])[N:22]1[C:23]1[CH:28]=[C:27]([F:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:37]=2)[CH3:32])[N:24]=1)[CH3:45])([CH3:15])([CH3:16])[CH3:14]
Reactant: C[C@H](Nc1nc(F)cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](Nc1nc(F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
Triphosgene (18 mg, 0.062 mmol, 0.5 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (57 mg, 0.12 mmol) in DCM (1.2 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.058 mL, 0.49 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 30 min. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 487.4 (M+H)+; Rt-1.12 min.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:9](=[C:10]([OH:22])[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]=3[OH:21])[C:8]2=[O:23])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:8](=[O:23])[C:9]3[C:18](=[C:17]([OH:21])[C:16]4[N:15]=[CH:14][CH:13]=[N:12][C:11]=4[C:10]=3[O:22][C:33](=[O:34])[O:35][CH2:36][CH3:37])[C:19]2=[O:20])=[CH:4][CH:3]=1
Reactant: O=C1c2c(c(O)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)Oc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 98 %

Procedure:
7-(4-Fluoro-benzyl)-5,9-dihydroxy-pyrrolo [3,4-g]quinoxaline-6,8-dione 242 (1 g, 2.95 mmol, 1 equiv.) was dissolved in DMF (30 ml, 0.1 M) and pyridine (477 μL, 5.89 mmol, 2 equiv.) before ethyl chloroformate was added (237 μL, 2.95 mmol, 1 equiv.). The reaction was stirred for 16 hours before being quenched with HCl (30 ml, 1 N) and extracted with ethyl acetate (2×30 mL). The organic layer washed several times with water (4×30 mL), saturated NaHCO3 (50 mL), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization was carried out in ethyl acetate and Hexanes to yield carbonic acid ethyl ester 7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ester 243 as a light brown solid (98%, 1.20 g, 2.89 mmol). 1H NMR (300 MHz) CDCl3 δ 9.09 (d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H), 7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H), 4.04 (q, J=2.8 Hz, 2 H), 1.43 (q, J=2.8 Hz, 3 H). MS: 412.6 (M+1).
Reaction SMILES: [CH:1]#C.[C:3]([O:7][K])([CH3:6])([CH3:5])[CH3:4].[C:9]1(=[CH:14][CH2:15]CC(=O)C)[CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[C:9]1(=[CH:14][CH2:15][CH2:4][C:3]([CH3:6])([OH:7])[C:5]#[CH:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#C
Reactant: CC(=O)CCC=C1CCCC1
Reactant: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: C#CC(C)(O)CCC=C1CCCC1
Temperature: 25 °C
Yield: 81 %

Procedure:
Acetylene was bubbled for 50 minutes through a solution of tBuOK (33.8 g; 0.30 mol) in THF (240 ml) at 0° C. The resulting beige suspension was treated with 5-cyclopentylidenepentan-2-one (41.7 g; 0.27 mol) added dropwise for 15 minutes at 0° C. The resulting mixture was warmed gently to room temperature and quenched with saturated NH4Cl (180 ml). The aqueous phase was separated and extracted with MTBE (2×120 ml). The combined organic layers were washed with H2O (240 ml), brine (100 ml), dried over MgSO4, and concentrated in vacuo. Distillation (69° C.-71° C./0.09 torr) afforded 38.95 g (81% yield) of 6-cyclopentylidene-3-methylhex-1-yn-3-ol.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:8]2[C:9](=[O:14])[NH:10][C:11](=O)O[C:7]=2[CH:6]=[CH:5][CH:4]=1.O>C(N)=O>[Br:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:8]=1[C:9](=[O:14])[NH:10][CH:11]=[N:1]2
Reactant: N
Reactant: O=c1[nH]c(=O)c2c(Br)cccc2o1
Solvent: O
Solvent: NC=O
Product: O=c1[nH]cnc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1. Gaseous ammonia is introduced at 15° to 25° C. into a suspension of 43 g of 5-bromo-2H-1,3-benzoxazine-2,4(1H)-dione in 190 ml of formamide. A solution thereby results. The solution is stirred at room temperature for 3 h. and then the excess ammonia is driven off by passing nitrogen through the solution. The solution is then stirred at 15° C. for 15 h. The reaction solution is then cooled and treated with 250 ml of water while stirring. The crystals are filtered off, washed with water and dried in a vacuum. 26 g of 5-bromo-3H-quinazolin-4-one of m.p. 239°-240° C. are obtained.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=O)[O:2]1.C1C[O:15][CH2:14][CH2:13]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:5]=[CH:13][CH:14]=[O:15])[CH:7]=[CH:8][CH:9]=2)[O:2]1
Reactant: C1CCOC1
Reactant: O=Cc1cccc2c1OCO2
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: O=CC=Cc1cccc2c1OCO2
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-methylenedioxybenzaldehyde (150 mg) in 5 mL THF was added 22 mg of ZnBr2. With stirring, 250 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (22 mg) in diethyl ether/water (5 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a brown oil (150 mg): 1H NMR (CDCl3) δ 6.09 (s, 2H), 6.14 (s, 1H), 6.86-6.98 (m, 4H), 7.43 (d, 1H, J=9.6 Hz), 9.69 (d, 1H, J=4.5 Hz).
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([OH:29])[CH2:23]2)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[OH-:33].[Ca+2].[OH-]>O>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@@H:22]([OH:27])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:33])=[C:9]([CH:30]([CH3:31])[CH3:32])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Reactant: [OH-]
Agent: [Ca+2]
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
E-6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (4.0 g), water (20.0 mL), and calcium hydroxide (0.64 g) was added to a reactor. The reaction mixture was stirred at room temperature for 3 hours and then filtered under reduced pressure. The resulting white solid was dried to obtain E-7-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid 1/2 calcium salt (4.1 g, yield 95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[C:4]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:3]1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(=O)[nH]cnc21
Solvent: CN(C)c1ccccc1
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Temperature: 0 °C

Procedure:
To a mixture of 5.0 grams of 1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 100 milliliters of phosphorus oxychloride were slowly added 48 grams of N,N-dimethylaniline. The mixture was heated under reflux for 2 hours, cooled and carefully added to 1 kilogram of crushed ice. The crystalline product was collected, washed with ether and dried. Recrystallisation from ethyl acetate gave 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having melting point 195°C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Br:29][CH:30](Br)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][Br:29])=[CH:32][CH:33]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(Br)Br)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1ccc(CBr)cc1)Nc1c(C(C)C)cccc1C(C)C
Yield: 39.1 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 8.7 g (0.033 mole) of α,α-dibromo-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent to obtain a slightly brown powder. The powder was then recrystallized from acetone to obtain 6.6 g of white powder.