Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH:20]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH2:24][CH2:23]1>>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH2:20][N:36]2[CH2:35][CH2:34][N:33]([C:30]3[CH:29]=[CH:28][C:27]([C:26]([NH:25][CH:22]4[CH2:24][CH2:23]4)=[O:39])=[CH:32][CH:31]=3)[CH2:38][CH2:37]2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Product: CC1Oc2c(Cc3ccccc3)cc(CN3CCN(c4ccc(C(=O)NC5CC5)cc4)CC3)cc2NC1=O

Procedure:
Using 353A and N-cyclopropyl-4-(piperazin-1-yl)benzamide 284 in the general procedure for reductive aminations, the title compound was obtained as a light grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.55 (m, 2H) 0.62-0.69 (m, 2H) 1.31 (d, J=6.82 Hz, 3H) 2.42-2.49 (m, 4H) 2.75-2.82 (m, 1H) 3.17-3.25 (m, 4H) 3.38 (s, 2H) 3.89 (s, 2H) 4.57 (q, J=6.74 Hz, 1H) 6.73-6.82 (m, 2 H) 6.91 (d, J=9.09 Hz, 2H) 7.14-7.19 (m, 1H) 7.19-7.24 (m, 2H) 7.24-7.30 (m, 2H) 7.69 (d, J=9.09 Hz, 2H) 8.14 (d, J=4.04 Hz, 1H) 10.60 (s, 1H). ESI-MS: m/z 511.4 (M+H)+. mp=192.3-203.2° C.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:14]C(Cl)(Cl)Cl>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>[Br:14][C:3]([CH2:1][CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClC(Cl)(Cl)Br
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Product: CCOC(=O)C(Br)(CC)C(=O)OCC
Yield: 93.6 %

Procedure:
In a 10 mL round-bottom flask, 1.88 g of diethyl ethylmalonate (10 mmol), 2.18 g of bromotrichloromethane (11 mmol), 79 mg of tetra-n-butylammonium fluoride trihydrate (0.25 mmol), and 69 mg of potassium carbonate (0.5 mmol) were stirred at 24° C. for 1 h. An exothermic reaction caused the temperature of the mixture to rise to 40° C. After filtration of the solids, the solution was found to contain 2.5 g (95% yield) of diethyl α-bromo-α-ethylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[O:24][CH:25]=[N:26][N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:24][C:25]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:15])=[N:26][N:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(Cc2nnco2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carb aldehyde and 2-benzyl-[1,3,4]oxadiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=1.O.[OH-].[Li+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCC(C)=O)c2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)COc1cccc(COc2ccc(CCC(=O)O)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
To a solution of ethyl 3-(3-fluoro-4-{[3-(2-oxopropoxy)benzyl]oxy}phenyl)propanoate (0.31 g, 0.82 mmol) in ethanol-water (2 mL-1 mL) was added lithium hydroxide monohydrate (0.052 g, 1.23 mmol), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 2 N hydrochloric acid (0.7 mL), and extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.047 g, yield 17%) as white powders.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:26]4[CH:25]=[C:24]5[C:27]([CH3:35])([CH3:34])[C:28]6[C:33]([C:23]5=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:32][CH:31]=[CH:30][CH:29]=6)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:36]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:41]=[CH:40][C:39]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:46]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:45]=[CH:44][C:43]([N:42]([C:39]2[CH:40]=[CH:41][C:36]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:37][CH:38]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[C:26]5[CH:25]=[C:24]6[C:27]([CH3:35])([CH3:34])[C:28]7[C:33]([C:23]6=[CH:22][C:21]=5[C:20]5[C:15]4=[CH:16][CH:17]=[CH:18][CH:19]=5)=[CH:32][CH:31]=[CH:30][CH:29]=7)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:48][CH:47]=1
Reactant: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(Br)cc5)cc4)c3cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(N(c6ccc(-c7ccccc7)cc6)c6ccc(-c7ccccc7)cc6)cc5)cc4)c3cc21
Yield: 45.9 %

Procedure:
10 g (19.4 mmol) of 10-(4′-bromobiphenyl-4-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 300 ml of toluene with 9.6 g (30 mmol) of bis(4-biphenylyl)amine and degassed. 1.94 ml (1.94 mmol/1 M in toluene) of tri-tert-butylphosphine, 252 mg of Pd(OAc)2 and 4.1 g (41.7 mmol) of NaOt-Bu are added, and the mixture is stirred under reflux for 10 h. The mixture is filtered through Alox B (activity grade 1), washed with water, dried and evaporated. The crude product is extracted with toluene in a Soxhlet extractor, recrystallised from toluene/heptane, giving 6.7 g (8.9 mmol, 46%) of the product as a yellow solid. Finally, the product is sublimed in a high vacuum, the purity is 99.9%.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH:18]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:10]=2[N:1]=1)[CH3:17]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(n1)NCCC2
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc2c(n1)NCCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbaldehyde (4-7, 2 g, 12.34 mmol) and (carbethoxymethylene)triphenylphosphorane (4.3 g, 12.34 mmol) in toluene (60 mL) was heated to reflux for 4 hours and stirred at ambient temperature for 12 hours. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% EtOAc/hexanes) to give 4-8 as a yellow solid.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1
Reactant: COCc1nccc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COCc1nccc(Cl)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
47 g (335.7 mmol) of 4-hydroxy-2-methoxymethylpyrimidine (from stage a) are mixed with 210 ml of phosphorus oxychloride and stirred at 70° C. for 2 h and subsequently heated to boiling for 2.5 h. The excess phosphorus oxychloride is removed by distillation in vacuo, the residue is hydrolyzed with ice, and solid potassium bicarbonate is added to eliminate excess acid. Several extractions with methylene chloride are carried out, and the organic phase is evaporated in vacuo. The black residue is filtered through silica gel (n-heptane/ethyl acetate 1:1). 15.7 g of oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:20]=[C:5]2[C:6]([O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:1][C:2]3[N:20]=[C:5]4[C:6]([O:10][CH2:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: N#Cc1ccccc1COc1cccn2nc(N)nc12
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)cc2)CC1

Procedure:
262 b) 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}benzonitrile was prepared from 2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-benzonitrile (115.0 mg, 0.434 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (128 mg, 0.500 mmol) in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.101 g, 53%). MP=156-157° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.32 (s, 1H), 8.40 (d, J=6.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.80 (d, J=4.5 Hz, 2H), 7.62-7.60 (m, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 6.98-6.88 (m, 3H), 5.49 (s, 2H), 3.04-3.02 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H). MS=440 (MH)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[C:48]1([CH2:54][CH:55]([C:57]2[N:61]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:60]=[N:59][CH:58]=2)[NH2:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:56][CH:55]([C:57]1[N:61]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:60]=[N:59][CH:58]=1)[CH2:54][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:38]
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccc(O)cc12)NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 9D (26.5 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.6 Hz, 2H), 7.21-7.01 (m, 6H), 6.96 (s, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.78 (d, J=6.8 Hz, 2H), 6.68 (dd, J=8.6, 2.3 Hz, 1H), 5.46 (s, 2H), 5.21 (t, J=7.6 Hz, 1H), 2.96 (ddd, J=21.5, 13.3, 7.6 Hz, 2H); MS (m/z) 438 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[S:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][N:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][N:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2nnc(C(F)(F)F)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI−): m/z=550 [M+HCOO]−.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH2:12][Br:15]
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1CBr
Reaction time: 14 h
Yield: 88.9 %

Procedure:
A 500 mL round bottomed flask was charged with 250 mL of carbon tetrachloride 15.90 g. of 2-(trifluoromethyl)-6-nitrotoluene, 27.60 g. of N-bromosuccinimide, and 11.8 g of benzoyl peroxide. This mixture was brought under reflux and stirred at this temperature for 14 h. The mixture was cooled, filtered and 9.94 g of N-bromosuccinimide together with 4.2 g of benzoyl peroxide was added to the filtrate. This mixture was brought under reflux for 14 h. The mixture was cooled, filtered and the filtrate was stripped of solvent. The crude product was chromatographed on a SiO2 column to give 19.57 g (88.9% yield) of pure product.
Reaction SMILES: [O-:1][Mo:2]([O-:5])(=[O:4])=[O:3].[Na+:6].[Na+].[Mo]=[O:9]>[OH-].[Na+]>[OH2:1].[OH2:9].[O-:4][Mo:2]([O-:5])(=[O:3])=[O:1].[Na+:6].[Na+:6]
Reactant: O=[Mo]
Agent: O=[Mo](=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O

Procedure:
Solid Sodium Molybdate (Na2MoO4) may be prepared by dissolving MoO3 in a basic aqueous solution of sodium hydroxide (NaOH) and crystallizing the filtered product to yield sodium molybdate dihydrate (Na2MoO4.2H2O). The anhydrous salt may be prepared by heating to a sufficient temperature to liberate the water.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[OH-].[Na+].Cl.[Cl-].[Na+]>CO>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:25]([F:28])([F:26])[F:27])[CH:3]=1
Reactant: COC(=O)c1ccn(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ccc(C(=O)O)n2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A solution of methyl 1-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-1H-pyrazole-3-carboxylate (320 mg, 0.8 mmol) (i.e. the product of Example 18, Step D) in 8 mL of methanol was cooled to 0° C. and 1 M aqueous sodium hydroxide solution (1.6 mL, 1.6 mmol) was gradually added. The reaction mixture was stirred at 50° C. for 16 h, and 1 M aqueous hydrochloric acid (1.6 mL, 1.6 mmol) was added followed by 5 mL of saturated aqueous solution of sodium chloride. The resulting mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and evaporated in vacuo to give 270 mg of the title compound as a glassy solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:3]3[N:4]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)=[CH:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(-c2cnc3c(N4CCN(C)CC4)nccn23)n1

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (1.36 g, 4.91 mmol) in iPrOH (100 mL) was added 1-methylpiperazine (0.64 g, 6.38 mmol) followed by diisopropylethylamine (0.82 g, 6.38 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (150 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4-methyl-piperazin-1-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine. (Yield 1.4 g, 83.7%). LC-MS: [M+H]+ 342.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].O.Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:5]([CH3:6])[C:4]([OH:23])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
17.5 g of 2-[p-(2,4-dichlorobenzyl)-phenoxi]-propionic acid ethyl ester were refluxed for 2 hours with a solution of 2.5 g of caustic soda in 100 ml of methanol. After cooling, 100 ml of water were added and the mixture was acidified with 2n hydrochloric acid. The propionic acid liberated precipitated in the form of a colorless oil which, on cooling in icewater, solidified to become a colorless wax-like mass. The yield is 15.3 g. ##STR11##
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7](=[O:27])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)[CH:12]=3)=[C:9]([OH:10])[C:4]=2[C:3]=1[CH3:29].[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7](=[O:27])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=4)[CH:12]=3)=[C:9]([OH:10])[C:4]=2[C:3]=1[CH3:29]
Reactant: Cc1c(Cl)sc2[nH]c(=O)c(-c3cccc(Oc4cccc([N+](=O)[O-])c4)c3)c(O)c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(Cl)sc2[nH]c(=O)c(-c3cccc(Oc4cccc(N)c4)c3)c(O)c12

Procedure:
20 mg of platinum oxide are added to a solution of 4.28 g of 2-chloro-3-methyl-4-hydroxy-5-(3-m-nitro-phenoxyphenyl)-6,7-dihydrothieno[2,3-b]pyridin-6-one in 50 ml of 95% ethanol. Hydrogen is passed through the solution until three molar equivalents have been absorbed. The platinum is filtered off and the alcohol is distilled off. 2-Chloro-3-methyl-4-hydroxy-5-(3-m-aminophenoxyphenyl)-6,7-dihydrothieno[2,3-b]pyridin-6-one is obtained.
Reaction SMILES: [Si](O)(O)(O)[OH:2].C(O[Si](OCC)(OCC)OCC)C.[P:19]([O-:23])([O-:22])([O-:21])=[O:20].[Ca+2:24].[P:25]([O-:29])([O-:28])([O-:27])=[O:26].[Ca+2].[Ca+2]>O.Cl>[OH-:2].[O-:21][P:19]([O-:23])([O-:22])=[O:20].[O-:27][P:25]([O-:29])([O-:28])=[O:26].[O-:21][P:19]([O-:23])([O-:22])=[O:20].[Ca+2:24].[Ca+2:24].[Ca+2:24].[Ca+2:24].[Ca+2:24]
Reactant: O[Si](O)(O)O
Agent: CCO[Si](OCC)(OCC)OCC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: [OH-]

Procedure:
For generating silicic acid, tetraethoxy silane (TEOS, 99%, Sigma) is hydrolyzed by addition of water and hydrochloric acid (10 mmol) as catalyst at 4° C. for 24 hours. The molar ratio of tetraethoxy silane to water is 1:4. This solution serves as the silicate component and is supplied to the collagen suspension that is enriched with calcium phosphate and is mixed intensively. After a few minutes a hydrogel is formed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Br:24])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CN(C)C(=O)c1cc(CCO)ccc1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(CCBr)ccc1OCc1ccccc1
Yield: 34.2 %

Procedure:
To a stirred solution of 2-benzyloxy-5-(2-hydroxyethyl)-N,N-dimethylbenzamide (300 mg) in dichloromethane (5 ml) were added carbon tetrabromide (366 mg) and triphenylphosphine (289 mg) at room temperature, and the mixture was stirred for minutes. After concentration of the reaction mixture under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) gave 2-benzyloxy-5-(2-bromoethyl)-N,N-dimethylbenzamide (124 mg). 1H-NMR(CDCl3) δ ppm: 2.86 (3H, s), 3.00-3.15 (2H, m), 3.11 (3H, s), 3.45-3.60 (2H, m), 5.11 (2H, s), 6.90 (1H, d, J=8.3 Hz), 7.05-7.20 (2H, m), 7.25-7.40 (5H, m)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].[Br:24]Br.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[Br:24])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Reactant: BrBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid methyl ester (0.720 g, 2.13 mmol) was dissolved in chloroform (20 mL) and bromine (0.511 g, 3.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h then concentrated under vacuum. The product was dissolved in dichloromethane (20 mL), treated with triethylamine (0.430 g, 4.26 mmol), stirred at ambient temperature for 2 h, and then concentrated under vacuum. The product was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient) to provide the title compound (0.5 g, 56% yield over two steps) as a white solid, mp 171-173° C.: 1H NMR (CDCl3) δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.22 (d, 1H), 6.72 (d, 1H), 5.37 (br s, 2H), 4.0 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][NH2:14]>O1CCOCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[N:12][C:2]=1[NH:13][NH2:14])[CH3:8]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: NN
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1NN
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of ethyl 2-chloronicotinate (10.0 g, 53.9 mmol) and anhydrous hydrazine (2.04 g, 63.8 mmol) in anhydrous 1,4-dioxane (200 mL) was stirred at 60° C. for 2 h. Analysis by LC/MS indicated the starting material was not consumed. Additional amount hydrazine (2.04 g, 63.8 mmol) was added and the reaction mixture was stirred at 60° C. overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The obtained residue was triturated with MeOH (35 mL), the insoluble white solid was removed by filtration and discarded. The methanol solution was concentrated in vacuo to yield a fluffy yellow solid which was triturated in diethylether to yield the title compound as an orange solid (5.4 g, 55%). HPLC/MS (Method D): retention time=1.46 min, [M+H]+=182.3.