Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:21][C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[C:11](=[O:14])[C:12]2[N:13]3[CH2:2][CH2:3][S:4][C:5]3=[N:6][C:7]=2[N:8]([CH3:23])[C:9]1=[O:22]
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(SCCCl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCS3)n(C)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A mixture of (R)-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (76 mg, 0.21 mmol) and potassium carbonate (58 mg, 0.42 mmol) in acetonitrile (15 ml) was stirred at 80° C. for 2 hours. After concentrating under reduced pressure, the residue was purified by column chromatography eluting with ethyl acetate-hexane (1:1) to provide (R)-6,7-dihydro-3-(5-hydroxyhexyl)-1-methyl-thiazolo[2,3-f]purine-2,4 (1H,3H)-dione (CT 13421) (22 mg, 32% yield) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([CH3:12])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(O)C(=O)Nc2cc(Br)ccc21
Solvent: C1CCOC1
Product: Cc1c[nH]c2cc(Br)ccc12
Temperature: 60 °C

Procedure:
A mixture of 6-bromo-3-hydroxy-3-methyl-1,3-dihydro-2H-indol-2-one (0.25 g, 1.0 mmol) and BH3—S(CH3)2 (5.16 mL. 1.0 M, 5.16 mmol) in THF (20 mL) was heated at 60° C. The reaction was quenched with MeOH. Volatiles were removed. Chromatography over silica eluting with 4:1 hexane:EtOAc afforded the title compound. LC-MS: calculated for C9H8BrN: 210.07, observed m/e 211.0 (M+H)+ (Rt 1.14 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH:24]([O:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]>>[CH:24]([O:27][C:28]1[C:33]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Oc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)Oc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 59 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-isopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were reacted to give 239 (0.102 g, 59%). 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=2.2, 1H), 8.23-8.03 (m, 2H), 7.75 (dd, J=7.3, 1.8, 1H), 7.56 (dd, J=8.4, 2.2, 1H), 7.20-7.00 (m, 2H), 5.72 (dt, J=13.3, 6.6, 1H), 5.35 (dt, J=12.3, 6.2, 1H), 4.43 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.50 (d, J=6.6, 6H), 1.29 (d, J=6.2, 6H). MS (ESI(+)): m/z 448.1 (M+H)
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]>CN(C=O)C>[N:1]1([CH2:17][C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:24][CH2:25]2)=[O:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc21)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzimidazole (0.785 g, 0.7 mmol) was taken in dry DMF (15 ml) and dry potassium carbonate (340 mg) and KI (20 mg) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration gave material that on purification by flash chromatography (CHCl3/MeOH) afforded pure product: 1H NMR (300 MHz, CDCl3): δ 8.10–7.65 (m, 4H), 7.26 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.79–3.66 (m, 4H), 3.14 (br, 4H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[N:13][C:12]=2[O:21][CH2:22][CH2:23][O:24][CH:25]([F:27])[F:26])[CH2:5][CH2:4]1>[Ni].[H][H]>[F:29][C:2]([F:1])([F:30])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[N:13][C:12]=2[O:21][CH2:22][CH2:23][O:24][CH:25]([F:26])[F:27])[CH2:7][CH2:8]1
Reactant: Nc1nc(OCCOC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCCOC(F)F)nc1N

Procedure:
The sub-title compound is prepared from N-(trans-4-trifluoromethyl-cyclohexyl)-2-(2-difluoromethoxy-ethoxy)-6-amino-5-nitro-nicotinamide (150 mg, 0.339 mmol), Ra—Ni/H2 (3 bar) in analogy to example 7b.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[O:5]([C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH2:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(N(CC)CC)C.O1CCOCC1>[O:5]([C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH:14][C:3]([NH:2][CH3:1])=[O:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cc(Cl)c(Cl)cc1Oc1ccccc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)Nc1cc(Cl)c(Cl)cc1Oc1ccccc1
Reaction time: 15 h

Procedure:
2.0 gm (35 mmols) of methylisocyanate and two drops of triethylamine are added to a solution of 6.35 gm (25 mmols) of 2-phenoxy-4,5-dichloroaniline in 50 ml of anhydrous dioxan. The resulting solution is kept at 50°-60° C. for 15 hours. Then about 40 ml of dioxan are distilled off in vacuo and the residue is stirred with 50 ml of petrol. After cooling to 5°-10° C. for one hour, the crystalline product is suction filtered, washed with 20 ml of petrol and dried.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]1[N:58]=[N:59][N:60]=[C:52]1[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:41])[CH3:40].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]1[N:58]=[N:59][N:60]=[C:52]1[CH:51]=[CH:50]2)[C:45]([OH:6])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)acetic acid (4.9 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)ethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) 8.61 (s, 1 H), 7.75 (d, J=9.6 Hz, 1 H), 7.67-7.55 (m, 4 H), 7.39 (d, J=9.2 HZ, 1 H), 5.2 (s, 1 H), 2.79 (s, 3 H), 1.00 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C22H22ClN4O3: 425.1. Found: 425.1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH:28]([CH2:32][CH3:33])[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:32]([CH:28]1[O:29][CH2:30][CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][N:23]=2)[CH2:27]1)[CH3:33]
Reactant: CCC1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CCO1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCC1CN(Cc2nnc(-c3cc(-c4cnc(OC)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)o2)CCO1
Temperature: 100 °C
Yield: 7.3 %

Procedure:
6-Bromo-4-{5-[(2-ethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (170 mg, 0.319 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (115 mg, 0.351 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (46.7 mg, 0.064 mmol) and potassium phosphate tribasic (203 mg, 0.958 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (5 ml) and water (0.5 ml). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give a yellow solid. The solid was purified further by high pH MDAP (Method E) and the appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (12 mg).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.O>O1CCCC1.CCCCCC>[O:20]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)c1cccnc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccnc1)OC
Reaction time: 1.33 h
Yield: 68.8 %

Procedure:
In argon atmosphere, 15.19 g of dimethyl methylphosphonate was dissolved in 170 ml of dry tetrahydrofuran, followed by dropwise addition of 1.55M n-butyl lithium solution in hexane at -78° C., which was then stirred at the same temperature for 80 minutes. Methyl nicotinate (16.79 g) dissolved in 50 ml of dry tetrahydrofuran was added dropwise and stirred at -78° C. for 20 hours, followed by addition of water. The organic solvent was distilled off under reduced pressure, which was extracted with methylene chloride. Alternatively, 2N hydrogen chloride was added to aqueous phase for neutralization, which was then extracted with ethyl acetate. The organic phase was washed in saturated aqueous sodium chloride, and dried over magnesium sulfate, to distill off the solvent under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v), 19.30 g of dimethyl 2-oxo-2-(3-pyridyl)ethylphosphonate was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[CH2:19][CH2:18][CH2:17][CH:13]2[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCN1c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (9 g, 40 mmol), L-proline (4.6 g, 40 mmol), and potassium carbonate (7 g, 50 mmol) in ethanol (50 ml) and water (40 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with 1N aqueous HCl solution. The mixture was extracted with EtOAc (2×100 mL), the combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to afford N-(5-bromo-2-nitro-phenyl)-pyrrolidine-2-carboxylic acid (6 g, 48%) which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]([C:9]([CH3:19])([CH3:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([CH3:8])[O:4]1.[OH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>C(O)C.[I-].[K+]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([C:5]2([CH3:8])[O:4][CH:3]([CH2:2][N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][OH:20])[CH2:23]3)[CH2:7][O:6]2)([CH3:19])[CH3:18])=[CH:12][CH:13]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(C)OCC(CCl)O1
Reactant: OCC1CCCNC1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(Cc1ccc(Cl)cc1)C1(C)OCC(CN2CCCC(CO)C2)O1
Yield: 99.5 %

Procedure:
30.3 g (0.1 mol) of 4-chloromethyl-2-[1-(4-chlorophenyl)-2-methyl-prop-2-yl]-2-methyl-1,3-dioxolane, 23 g (0.2 mol) of 3-hydroxymethylpiperidine and 0.1 g of potassium iodide in 100 ml of ethanol are heated at 150° C. under pressure (2 bar) for 15 hours. For working up, the solvent is removed in vacuo, the residue is taken up in 100 ml of methylene chloride, the mixture is washed twice with 100 ml of water each time and dried over sodium sulphate and the solvent is removed again in vacuo. 38 g (100% of theory) of 2-[1-(4-chlorophenyl)-2-methyl-prop-2-yl]-4-[(3-hydroxymethylpiperidin-1-yl)-methyl]-2-methyl-1,3-dioxolane of refractive index n20 1.5226 are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]([NH2:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([NH:36][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC(C)(C)CC(C)(C)C)c(=O)n12
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml chloroform is dropped to the above mixture at a temperature between -12° C. and -18° C. during 20 minutes. After stirring for 5 minutes, 11.37 g (0.088 mol) of tert.-octylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -18° C. and -15° C. during 40 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 16.1 g (63.8%) of the named product as light yellow crystals after recrystallization from ethanol, m.p.: 126°-129° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:14][C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:14][C:15]([CH:17]2[CH2:18][CH2:19]2)=[O:16])=[N:6][C:7]=1[C:8]1[CH:9]=[N+:10]([O-:28])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cnc(Br)c(-c2cccnc2)n1)C1CC1
Solvent: ClCCl
Product: O=C(Nc1cnc(Br)c(-c2ccc[n+]([O-])c2)n1)C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To a suspension of N-(5-bromo-6-pyridin-3-ylpyrazin-2-yl)cyclopropanecarboxamide (4.02 g, 12.6 mmol) in CH2Cl2 (45 mL), cooled at 0° C., was added mCPBA (3.11 g, 12.6 mmol) in small portions. Upon addition completion the ice bath was removed and the reaction continued at room temperature for 4 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3 (1×25 mL) and saturated NaCl (1×25 mL). The organic layer was concentrated in vaccuo up to 25 mL volume, and the precipitated product was filtered and washed with Et2O (4×5 mL), giving the title compound as a white powder (3.03 g, 72% yield).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>O>[CH3:25][S:24][C:20]1[N:21]=[C:22]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH:23]=[CH:18][N:19]=1
Reactant: CSc1nccc(Cl)n1
Reactant: c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-n2nnc3ccccc32)n1
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
A 1 L round bottom flask was loaded with sodium hydride dispersion (10.0 g, 250 mmol, 60% in mineral oil) and 200 mL of DMF, and the resulting slurry cooled with an ice bath. Benzotriazole (18.02 g, 151 mmol) was added portionwise over a 10-12 min period. The reaction mixture was stirred for 10 min to allow gas evolution to subside; the ice bath was then removed and 4-chloro-2-methylthiopyrimidine (24.07 g, 150 mmol) was added. The resulting mixture was stirred at RT for 15 minutes, then placed in a 90° C. oil bath for 1.5 hour. The heating bath was turned off and the reaction mixture was allowed to slowly cool with stirring overnight. The reaction mixture was then poured into 500 mL of water and stirred for 20 min, and then filtered. The collected solids were washed with 3 portions of water and 3 portions of a mixture of hexanes/EtOAc (10:1 to 5:1), then dried to give 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazole as an off-white solid (27.05 g, 74% yield), mp=180.5-181.7° C.; MS=244 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[C:29](=[O:31])=[O:30]>C1COCC1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:29]([OH:31])=[O:30])=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: O=C=O
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
To a solution of 5-bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (WO 0183489) in THF (60 ml) was added isopropylmagnesiumcholride (2M solution in THF, 3.35 ml) dropwise at 0° C. under nitrogen. After 5 min the mixture was treated with a stream of carbon dioxide for 10 min. The reaction mixture was quenched with water, acidified 2N HCl and extracted into ethyl acetate (×3). The combined organic extracts were washed with dilute HCl, brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as a yellow solid (2.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (261 mg, 0.90 mmol) and lithium hydroxide (188 mg, 4.50 mmol in 3 mL H2O), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc to afford the title compound. 147 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.06-2.17 (m, 1H) 2.53-2.64 (m, 1H) 2.64-2.73 (m, 2H) 2.73-2.85 (m, 2H) 3.26-3.36 (m, 1H) 6.52 (d, J=1.32 Hz, 1H) 7.08 (dt, 1H) 7.19-7.26 (m, 3H) 8.87 (br. s, 1H). LCMS m/e 276 (M+H). Purity>98% (HPLC).
Reaction SMILES: [Na].C([O:4][C:5](=O)/[C:6](/[CH3:16])=[C:7](\[NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])/[CH3:8])C>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[NH:9][C:7]([CH3:8])=[C:6]([CH3:16])[C:5]=1[OH:4])=[O:12])[CH3:15]
Reactant: CCOC(=O)CN/C(C)=C(/C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1[nH]c(C)c(C)c1O
Yield: 78.2 %

Procedure:
Using the method described in Example 1, 35 g of sodium in 1.5 liters of ethanol, and 264 g of 3-(ethoxycarbonylmethylamino)-2-methylcrotonic acid ethyl ester in 400 ml of ethanol give 165 g of 3-hydroxy-4,5-dimethyl-pyrrole-2-carboxylic acid ethyl ester, of melting point 111°-113° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](O)[N:5]2[N:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:4]2[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:6]1[N:5]2[N:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:4]2[N:3]=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: COC(=O)c1nc2nc(C)c(C)c(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1nc2nc(C)c(C)c(Cl)n2n1
Yield: 186.3 %

Procedure:
To a suspension of the product obtained in Step 1 (50 g) in 500 ml of phosphorus oxychloride N,N-dimethylaniline (30 g) was dropwise added at room temperature, the mixture was refluxed for two hours, excess phosphorus oxychloride was removed by distillation under normal pressure, and the black oil left was dissolved in 200 ml of chloroform. This solution was slowly poured into 200 ml of ice-cooled saturated sodium bicarbonate solution, the chloroform layer was collected after thorough mixing, and the aqueous layer was again extracted with 200 ml of fresh chloroform. The combined organic layers were washed with 100 ml of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure to about 50 ml, and 100 ml of n-hexane was added to this concentrate, giving 49 g of the objective compound as colorless crystals.