Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[NH:22][CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[N:22]([CH2:32][C:33]5[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=5)[CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C

Procedure:
A mixture of methyl 4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.943 g, 2.93 mmol) in N,N-Dimethylformamide (DMF) (6.0 mL) was treated with cesium carbonate (1.906 g, 5.85 mmol) and then 4-(bromomethyl)-1,2-difluorobenzene (0.561 mL, 4.39 mmol) and the mixture was heated to 80° C. for 75 minutes. The mixture was cooled to ambient temperature, diluted with ethyl acetate and then washed with water and brine. The water that was used for washing was back extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford a pale yellow residue: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25-7.17 (m, 2 H), 7.14-6.99 (m, 3 H), 6.96 (ddd, J=2.0, 4.1, 6.2 Hz, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 6.44 (d, J=3.7 Hz, 1 H), 5.45 (s, 2 H), 4.30-4.20 (m, 2 H), 3.69 (s, 3 H), 2.84 (t, J=6.4 Hz, 2 H), 2.68 (s, 3 H), 2.14-1.96 (m, 2 H); LC/MS (m/z) ES+=449 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][N:7]=1.O=C1N[C:15](=[O:17])[CH:14]=NN1>C(OC(=O)C)(=O)C>[C:15]([N:6]1[C:5](=[O:8])[NH:4][C:3](=[O:9])[C:2]([Br:1])=[N:7]1)(=[O:17])[CH3:14]
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: O=c1[nH]nc(Br)c(=O)[nH]1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1nc(Br)c(=O)[nH]c1=O

Procedure:
The 6-bromo-3,5-dioxo-(2H,4H)-1,2,4-triazine (5 g) obtained from the 3,5-dioxo-(2H,4H)-1,2,4-triazine in accordance with the technique described in example 1b is treated with acetic anhydride (50 ml) for 7 hours under reflux. After concentration to dryness under vacuum and taking up in ethyl ether, the precipitate is filtered, centrifuged, and dried under vacuum at 50° C. to give compound 15a (4.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][C:25](=[O:28])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 2-(methoxycarbonyl)thiophene-3-sulphonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4H), 3.50 (t, J=6.0 Hz, 4H), 3.89 (s, 3H), 6.90 (d, J=9.1 Hz, 2H), 6.96 (d, J=9.1 Hz, 2H), 7.33 (d, J=6.9 Hz, 1H), 7.90 (d, J=6.9 Hz, 1H), 9.50 (s, 1H); MS (ES) m/z: 395.0 (MH+); HRMS Calcd. for C17H19N2O5S2 (MH+): 395.0736. Found: 395.0721.
Reaction SMILES: F[C:2](F)([CH2:17]C1C=CC=CC=1)[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])C(O)=O.FC(F)(F)C(O)=O.NC(CC)[C@@H](C1OC(C2CC2)=NN=1)O.[CH:46]1([C:49]2[O:53][C:52]([C:54]([CH:56]([NH:59][C:60]([CH:62](NC(N3CCOCC3)=O)[CH2:63][C:64]([F:73])([F:72])[CH2:65][C:66]3C=CC=C[CH:67]=3)=[O:61])[CH2:57][CH3:58])=[O:55])=[N:51][N:50]=2)[CH2:48][CH2:47]1>>[CH:46]1([C:49]2[O:53][C:52]([C:54]([CH:56]([NH:59][C:60]([C:62]3([CH2:17][CH2:2][CH2:3][CH2:4][NH:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:67]=[CH:66][CH2:65][C:64]([F:73])([F:72])[CH2:63]3)=[O:61])[CH2:57][CH3:58])=[O:55])=[N:51][N:50]=2)[CH2:48][CH2:47]1
Reactant: CCC(NC(=O)C(CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)c1nnc(C2CC2)o1
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CCC(N)[C@H](O)c1nnc(C2CC2)o1
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(=O)C1(CCCCNC(=O)N2CCOCC2)C=CCC(F)(F)C1)C(=O)c1nnc(C2CC2)o1

Procedure:
By proceeding in a similar manner to Example 1 above but using (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-butan-1-ol Trifluoro acetic acid salt, there is prepared morpholine-4-carboxylic acid {1-[1-(5-cyclopropyl-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-3,3-difluoro-4-phenyl-butyl}-amide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]>>[CH3:31][C:15]1([CH3:14])[O:20][C:19]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([N:2]([CH3:1])[CH2:3][C:4]3[N:5]([CH3:13])[C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:29])[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Yield: 64.5 %

Procedure:
According to the procedure of Example 43d, methyl-(1-methyl-1H-indol-2-ylmethyl)-amine (124 mg, 0.71 mmol) and 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (160 mg, 0.64 mmol), were coupled to yield the title compound (167 mg, 64%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 11.03-11.04 (m, 1H), 8.15-8.20 (m, 1H), 7.89-7.94 (m, 1H), 7.41-7.56 (m, 3H), 7.39-7.41 (m, 1H), 7.00-7.12 (m, 1H), 6.14-6.99 (m, 1H), 4.87-5.05 (m, 2H), 3.68-3.72 (m, 3H), 2.99-3.10 (m, 3H), 1.39-1.44 (m, 6H); MS (ESI) m/e 405 (C23H24N4O3+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=O)[O:29]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:29]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(Nc1ccccn1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.361 mmol) in MeCN (2 mL) was added 4-nitrophenyl pyridin-2-ylcarbamate (467 mg, 1.80 mmol). The resulting mixture was then heated at 70° C. for 16 h, cooled to RT and filtered. The white solid obtained was washed with DCM (2×2 mL). The combined filtrates were then concentrated and the residue purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][CH2:48][CH3:49])=[N:7][C:6]=1[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[CH2:53][CH2:52]1)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][CH2:48][CH3:49])=[N:7][C:6]=1[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[CH2:53][CH2:52]1)=[O:4]
Reactant: CCCc1nc(CN2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCCc1nc(CN2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
5-Methoxycarbonyl-4-[4-(2-pyridyl)-piperazin-1-yl]methyl-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole (1.72 g, 2.10 mmol), obtained from Part B of Example 101, was stirred in 75 mL methanol at reflux for 2 hours. After evaporation of solvent under reduced pressure, the residue was stirred in 30 mL of 1:1 methanol/5% aqueous NaHCO3 for 6 h. The reaction mixture was extracted with 4×50 mL ethyl ether, and the residual organic solvent in the aqueous layer was evaporated under reduced pressure. The product was precipitated by adjusting the pH to 5 with aqueous HCl. The title compound (1.02 g, 84.2%) was collected as a white powder after filtering and drying in vacuo at 60° C. 1H NMR (300 MHz, CDCl3): δ0.86 (t, J=7.3 Hz, 3H); 1.61 (m, 2H); 2.54 (t, J=7.7 Hz, 2H); 2.76 (br s, 4H, piperazine); 3.54 (br s, 4H, piperazine); 3.63 (s, 3H); 3.88 (s, 2H); 5.27 (s, 2H); 6.57-8.13 (m, 12H).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:17]1[C:36]([C:37]2[NH:41][N:40]=[CH:39][CH:38]=2)=[CH:35][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([Cl:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[O:22])=[CH:19][N:18]=1.O>CC(O)C>[Cl:34][C:31]([F:32])([F:33])[O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:35]=[C:36]([C:37]3[NH:41][N:40]=[CH:39][CH:38]=3)[C:17]([N:5]3[CH2:6][CH:3]([OH:2])[CH2:4]3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: OC1CNC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(-c2ccn[nH]2)c1
Temperature: 140 °C

Procedure:
3-Hydroxyazetidine hydrochloride (53.2 mg, 0.486 mmol) and DIPEA (0.170 mL, 0.972 mmol) were added to a suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.243 mmol) in iPrOH (0.5 mL) and the RM was heated at 140° C. for 3 h. The RM was treated with water, extracted with EtOAc, and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give. the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1) to give the title product as a yellow foam. HPLC (Condition 7) tR=5.518 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=436 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.49-3.57 (m, 2H) 3.87-3.99 (m, 2H) 4.32-4.44 (m, 1H) 5.53 (br.s, 1H) 6.40 (br.s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.81-7.91 (m, 3H) 8.06 (d, J=2.35 Hz, 1H) 8.70 (br.s, 1H) 10.23 (s, 1H) 13.01 (s, 1H).
Reaction SMILES: C=C1OC(=O)C1.BrBr.[CH:9]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:23][CH2:24][C:25](=[O:30])[CH2:26][C:27](Br)=[O:28]>C(Cl)Cl.C(N(CC)CC)C>[Br:23][CH2:24][C:25](=[O:30])[CH2:26][C:27]([O:22][CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:28]
Reactant: O=C(Br)CC(=O)CBr
Reactant: OC(c1ccccc1)c1ccccc1
Agent: BrBr
Agent: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In 10.5 ml of methylene chloride there were dissolved 2.1 g of diketene, and at a temperature not exceeding -30° C., a solution of 4.0 g of bromine in 12.5 ml of methylene chloride was added dropwise to the solution with stirring. After the dropwise addition was completed, the mixture was maintained at 0° C. for 10 minutes. Separately, 3.68 g of benzhydrol were dissolved in 25 ml of methylene chloride, followed by addition of 2.02 g of triethylamine. Under stirring at a temperature not exceeding -30° C., the solution of bromoacetoacetyl bromide prepared above was added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 40 minutes, at the end of which time it was washed with water. After drying over magnesium sulfate the solvent was distilled off under reduced pressure, whereupon 6.99 g of benzhydryl 4-bromo-3-oxobutyrate there were obtained.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].[OH-].[Na+]>C1COCC1>[CH3:12][NH:11][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 312.0 ([M−H]−, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:7]([F:16])=[C:8]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)[CH:9]=1)[CH3:2].[NH2:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>>[C:26]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:11](=[O:13])[CH:10]([C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[C:6]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:7]=2[F:16])[O:14][CH3:15])=[CH:29][CH:28]=1)#[N:25]
Reactant: CCOc1cc(OC2CCN(C)CC2)c(F)c(C(OC)C(=O)O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-[5-Ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-2-methoxy-acetamide. Colorless foam. MS 456.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[O:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2B(O)O)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]=2[O:10][CH2:11][CH2:12][CH2:13]3)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OB(O)c1cccc2c1OCCC2
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cnc(Cl)nc1-c1cccc2c1OCCC2
Temperature: 90 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
A batch with 2,4-dichloro-5-fluoropyrimidine (565 mg; 3.28 mmol; Aldrich Chemical Company Inc.), 3,4-dihydro-2H-chromen-8-ylboronic acid (643 mg; 3.61 mmol; Parkway Scientific LLC) and bis(triphenylphosphine)palladium(II)chloride (230 mg; 0.33 mmol; Aldrich Chemical Company Inc.) in 1,2-dimethoxyethane (5.4 ml) and 2M solution of potassium carbonate (4.9 ml) was degassed using argon. The batch was stirred under argon for 16 hours at 90° C. After cooling the batch was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 2%-20%) to give the desired product (701 mg; 2.57 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].CCCCCC.C([Li])CCC.Cl[Si:20]([CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]([C:3]1[CH:7]=[CH:6][CH:5]([Si:20]([CH:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)([CH3:22])[CH3:21])[CH:4]=1)[CH3:2]
Reactant: CCC1=CC=CC1
Reactant: C[Si](C)(Cl)C1C=CC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1=CC([Si](C)(C)C2C=CC=C2)C=C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ethylcyclopentadiene in an amount of 7.52 g (80 mmol) was dissolved in 100 ml of THF, and the solution was cooled to −78° C. A 1.58 M hexane solution of n-butyllithium in a volume of 56 ml (92 mmol) was added thereto dropwise. The mixture was stirred at room temperature for 2 hours and was added dropwise to 50 ml of THF containing 110 mmol of the chloro(cyclopentadienyl)dimethylsilane at −78° C. The temperature was gradually increased, and the mixture was stirred at room temperature for 24 hours and was concentrated under reduced pressure. Insolubles were removed by filtration. The filtrate was washed with hexane and was distilled under reduced pressure. The distillate was subjected to silica gel column chromatography, and 0.86 g of (3-ethylcyclopentadienyl)(cyclopentadienyl)dimethylsilane was obtained. The compound was identified by GC-MS. GC-MS: 216 (MS).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17]O)[CH:15]=3)[N:10]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:49])(=O)=O.C(OCC)(=O)C>C(Cl)Cl>[Cl:49][CH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCc1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CCl)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, a solution of 1.21 g of [3-(3-fluorophenyl)-1-trityl-1H-5-indazolyl]methanol in 12 ml methylene chloride were added 0.45 ml of triethylamine and 0.23 ml of methanesulfonyl chloride, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 150 ml of ethyl acetate. The mixture was sequentially washed with water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were recrystallized from diisopropyl ether, to give 1.13 g of the title compound as white crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH3:24])=[C:13]3[C:21](=O)[NH:20][CH2:19][C@@H:18]([CH3:23])[N:14]3[C:15]=2[C:16]=1[CH3:17].[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>C(O)C>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH3:24])=[C:13]3[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:23])[N:14]3[C:15]=2[C:16]=1[CH3:17]
Reactant: Cc1c2n(c3c(C)c(Cl)ccc13)[C@H](C)CNC2=O
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Product: Cc1c2n(c3c(C)c(Cl)ccc13)[C@H](C)CNC2
Yield: 45.1 %

Procedure:
Lithium aluminium hydride (64 mg, 1.67 mmol) was added in portions to a solution of (R)-7-chloro-4,6,10-trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (200 mg, 0.76 mmol) and the resulting suspension was heated to reflux for 5 h. After cooling the reaction was quenched by careful addition of 1 M aqueous sodium potassium tartrate solution (20 mL). Then ether (20 mL) was added; the organic layer was separated, washed with brine, dried (Na2SO4), and evaporated. The residue was dissolved in ether (3 mL) and treated with a solution of oxalic acid (200 mg, 2.22 mmol) in ethanol (1 mL). The precipitate was collected by filtration and dried to yield the title compound (116 mg, 45%). Off-white solid. ISP-MS: m/e=249.2 ([M+H−C2H2O4]+). Anal. calc. for C16H19ClN2O4 (338.79): C 56.72; H 5.65; N 8.27; found: C 56.64; H 5.41; N 8.22.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([Cl:24])=[C:20]([O:22][CH3:23])[CH:21]=2)[N:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([Cl:24])=[C:20]([O:22][CH3:23])[CH:21]=2)[N:3]=1
Reactant: COc1cc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)(C)O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-chloro-5-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (85 mg, 0.220 mmol) in 2 mL of THF at 0° C. was treated with methylmagnesium bromide (0.73 mL of 3.0 M solution in ether, 2.20 mmol) and stirred at this temperature for 15 min. It was quenched with ice cold saturated NH4Cl solution and extracted twice with EtOAc. The combined organic solution was concentrated and the residue was purified on a silica gel column and eluted with 50 to 100% EtOAc in DCM to give the title compound (23 mg, 26% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (br., 1H), 8.97 (d, J=2.6 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 5.21 (s, 1H), 3.94 (s, 3H), 2.47 (s, 3H), 1.49 (s, 6H). m/z (ESI, positive ion) 402.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]1[C:22]([O:24]CC)=[O:23].[OH-].[Li+]>C1COCC1.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=2)=[O:9])[CH:4]=[C:3]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1C(=O)O

Procedure:
470 mg (1.27 mmol) of ethyl 1-methyl-4-[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-1H-pyrrole-2-carboxylate are initially charged in 5 ml of THF, 152 mg (6.33 mmol) of lithium hydroxide in 1 ml of water are added and the mixture is stirred under reflux overnight. The reaction mixture is concentrated, the residue is acidified with 2M hydrochloric acid and the precipitate formed is filtered off with suction and dried under reduced pressure. This gives a solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1C=CC=CC=1>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:19]([NH:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN=C=O
Reactant: CCCCNc1nc(C)co1
Solvent: c1ccccc1
Product: CCCCCCNC(=O)N(CCCC)c1nc(C)co1

Procedure:
A solution of 2-butylamino-4-methyloxazole (10.0 g, 0.065 mol) and hexyl isocyanate (8.25 g, 0.065 mol) in dry benzene was heated under reflux for 3 hours. The solution was evaporated and the residual oil dissolved in ether, washed with dilute HCl, dried and re-evaporated. The residue was dissolved in petroleum spirit (40°-60° C.) carbon treated and re-evaporated under vacuum to give the pure product as a pale oil.