Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C:15]2[C:16](=[O:27])[NH:17][C:18](=[O:26])[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[C:20]=2[NH2:21])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[CH2:22]([N:19]1[C:20]2[N:21]=[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=3)[NH:14][C:15]=2[C:16](=[O:27])[NH:17][C:18]1=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(C)=O)cc2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
A solution of 2-(4-acetylamino-phenyl)-N-(6-amino-1-butyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetamide (330 mg, 0.88 mmol) in methanol (7.0 mL) was treated with a 10% aqueous sodium hydroxide solution (3.54 mL). The resulting solution was stirred at 25° C. for 5 min and then was heated to 50° C. for 3 h. At this time, another portion of a 10% aqueous sodium hydroxide solution (3.54 mL) was added. The reaction was heated to 50° C. for an additional 4 h. At this time, the reaction was concentrated in vacuo. The residue was cooled to 0° C. and then treated with a 1N aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to afford N-[4-(3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-phenyl]-acetamide (196 mg, 62%) as an orange-yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 13.32 (broad s, 1H), 10.96 (broad s, 1H), 9.94 (broad s, 1H), 7.48 (d, J=8.42 Hz, 2H), 7.17 (d, J=8.42 Hz, 1H), 3.95 (s, 2H), 3.86 (m, 2H), 1.99 (s, 3H), 1.59 (m, 2H), 1.27 (m, 2H), 0.87 (t, J=7.32 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:14][CH2:13]2)=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClCCl.[CH:28]([N:31]([CH2:35][CH3:36])[CH:32](C)C)(C)C.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>>[Cl:11][C:5]1[C:6]([C:7](=[O:9])[NH:15][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:36]([CH2:35][N:31]([CH3:28])[CH3:32])[CH:24]=2)=[CH:10][C:2]([NH:1][C:42]([C:38]2[O:37][CH:41]=[CH:40][CH:39]=2)=[O:43])=[C:3]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:16][CH2:17]2)[CH:4]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2N)CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCc3cccc(CN(C)C)c3)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 5-amino-2-chloro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 14a (107.50 mg, 0.31 mmol) was taken up in clean, dry, reagent grade dichloromethane (5.00 ml, 77.53 mmol) and the mixture was stirred until all solids were in solution. To this stirred solution was added the N,N-diisopropylethylamine (0.16 ml, 0.92 mmol) followed by the furan-2-carbonyl chloride (0.04 ml, 0.41 mmol) and the reaction was allowed to stir at room temperature overnight. The reaction was analyzed by LCMS, which showed that mixed anhydride had formed along with the desired compound. The reaction was then concentrated under reduced pressure and taken back up in methanol and the solution was then treated with saturated NaHCO3 solution and the mixture was stirred for 2 h. The mixture was then diluted with 20 ml of water and 20 ml of dichloromethane. The layers were separated and the product was extracted from the aqueous using dichloromethane (3×10 ml). The organic phases were combined, washed with brine (1×25 ml) and dried over MgSO4. The solution was filtered under vacuum and the collected solution was then concentrated under reduced pressure. The product, 2-chloro-5-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 14b (135.70 mg, 0.31 mmol), was isolated as a yellowish solid and was carried on without further purification. LCMS (m/e)=439 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]=[C:27]1[NH:32][CH2:31][CH2:30][CH2:29][N:28]1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:36]2[CH2:37][CH2:38][CH:33]([N:28]3[CH2:29][CH2:30][CH2:31][NH:32][C:27]3=[O:26])[CH2:34][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 144.4 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.378 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.22 g) by a method similar to that described in Example 8, to give the title compound (0.420 g); mp 165-175° C. (d); MS: m/z=545(M+1); NMR(CD3SOCD3): 1.65 (d,2, J=12), 1.78 (s,2), 2.18 (m,2), 3.08 (s,3), 3.8 (s,3), 4.78 (d,1, J=3.5), 6.77 (d,1, J=8.5), 7.01 (s,2), 7.18 (dd,1, J=8.3, 2.4), 7.35 (d,1, J=8.2), 7.8 (d,1, J=8.4). Analysis for C28H34Cl2N4O3.1.5 HCl.1.5 H2O: Calculated: C, 53.61; H, 6.18, N, 8.93; Found: C, 53.56; H, 6.01; N, 8.33.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([C:22]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[O:33])[CH2:26][CH2:25]3)=[O:23])[CH2:12][C:11]=2[CH:10]=[N:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([C:22]([CH:24]3[CH2:25][CH2:26][CH:27]([CH2:30][NH:31][C:32]([CH:34]4[CH2:35][CH2:36][N:37]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:38][CH2:39]4)=[O:33])[CH2:28][CH2:29]3)=[O:23])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: CC(C)C=O
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)C1CCC(CNC(=O)C3CCNCC3)CC1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN1CCC(C(=O)NCC2CCC(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of piperidine-4-carboxylic acid [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide hydrochloride (Compound number 238) (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=507.4
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[N:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:25]=[CH:26][C:27]=1[C:2]1[S:6][C:5]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nnc(Br)s2)CC1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a 5 mL microwave vial was added tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.29 mmol), 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (173 mg, 0.58 mmol), K3PO4 (153 mg, 0.72 mmol), and Pd(PPh3)4 (17 mg, 0.015 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min and heated to 100° C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to give 87 mg (68.5%) of tert-butyl 4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+1)=440.4; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (d, J=8.59 Hz, 1H), 8.03 (d, J=2.53 Hz, 1H), 7.78 (d, J=1.52 Hz, 1H), 7.62 (d, J=2.02 Hz, 1H), 7.32 (dd, J=2.02, 8.59 Hz, 1H), 6.59 (m, 1H), 6.51-6.55 (m, 1H), 4.15-4.22 (m, 2H), 4.11 (s, 3H), 3.69 (t, J=5.56 Hz, 2H), 2.78-2.90 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH:8]C(OC(C)(C)C)=O.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH2:8]
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#COC[C@H](N)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
N-tert-butoxycarbonyl O-propynyl L-seryl glycine methyl ester (2.52 g, 8.02 mmol) was dissolved in CH2Cl2 (15 mL). Trifluoroacetic acid (15 mL) was added and the reaction mixture stirred for 2 h at room temperature. The solvent and bulk of excess TFA were removed and the residue washed with Et2O (2×15 mL). The diethyl ether was decanted off and the residue dried under vacuum before being redissolved in CH2Cl2 (70 mL). The solvent was evaporated and the residue dried under high vacuum overnight affording a brown, viscous oil (2.32 g, 88%); δH (200 MHz; d6-DMSO) 8.97 (1H, t, J 6, NH), 8.31 (3H, br s, NH3+), 4.21 (2H, d, J 2, CH2CCH), 4.16-4.05 (1H, m, CαH(propSer)), 3.96 (2H, d, J 6, CαH2(Gly)), 3.83 (1H, dd, J 11 and 4, CHH), 3.74 (1H, dd, J 11 and 6, CHH), 3.65 (3H, s, OCH3), 3.55 (1H, t, J 2, CCH).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[C:23]3[C:22]4[CH2:21][CH2:20][CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+]>CO>[F:1][CH2:2][CH2:3][N:4]([CH3:28])[CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[C:23]3[C:22]4[CH2:21][CH2:20][CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: FCCNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(CCF)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
A solution of 1-N-(2-fluoroethyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.30 mmol, 1.00 equiv) in methanol (10 mL) was added HCHO (37%, 1 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The NaBH(OAc)3 (250 mg, 1.18 mmol, 4.00 equiv) was added and the resulting solution was stirred for additional 1 h at ambient temperature. After completion of the reaction, the reaction was then quenched with saturated aqueous sodium bicarbonate, extracted with 3×50 ml of dichloromethane. The combined organic layers were dried in an oven under reduced pressure and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/MeOH (10:1) to afford the corresponding 1-N-(2-fluoroethyl)-1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (47.8 mg, 46%) as a white solid. MS: (ES, m/z): 349 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 1.23-1.32 (m, 2H), 1.50-1.60 (m, 2H), 1.76-1.95 (m, 2H), 2.27-2.35 (m, 2H), 2.40 (s, 3H), 2.50-2.60 (m, 3H), 2.84 (d, 2H), 2.99-3.05 (m, 4H), 4.05-4.15 (m, 1H), 4.57 (d, 2H), 4.86 (d, 1H), 8.39 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][Br:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCCN1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC1CCCCN1Cc1ccccc1
Yield: 39.8 %

Procedure:
(RS)-(1-Benzyl-piperidin-2-yl)-methanol (R. Sreekumar et al, Tetrahedron Lett., 1998, 39 5151) (10.0 g) was converted to the title compound (5.2 g) by treatment with triphenylphosphine (13.0 g) and N-bromosuccinimide (9.4 g) in dichloromethane using literature procedures, (Tetrahedron Lett, 1999, 40, 7477-8).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Cl:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([NH:17][CH3:18])=[N:15][CH3:16])[S:11][CH:12]=1>Cl>[ClH:6].[ClH:1].[CH3:16][N:15]=[C:14]([NH:17][CH3:18])[NH:13][C:10]1[S:11][CH:12]=[C:8]([CH2:7][S:5][CH2:4][CH2:3][NH2:2])[N:9]=1
Reactant: CN=C(NC)Nc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: CN=C(NC)Nc1nc(CSCCN)cs1

Procedure:
Cysteamine hydrochloride (2.25 g; 19.6 mmoles) and 4-chloromethyl-2-(2,3-dimethylguanidino)thiazole (5 g; 19.6 mmoles) [prepared from 1,3-dichloro-2-propanone and (N,N'-dimethylamidino)thiourea which is itself prepared from dimethyl cyanodithioiminocarbonate and methylamine] were dissolved in 17.5 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100°. After 24 hours the reaction mixture was evaporated under reduced pressure and the residue crystallized from absolute ethanol to yield the title compound, mp 243°-245°.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19](Br)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][SiH:33]([CH3:37])C(C)C.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].CN1C[CH2:60][CH2:59][C:58]1=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([C:22]=3[SiH:33]([CH3:37])[CH3:32])=[CH:20][C:19]([CH:59]([CH3:60])[CH3:58])=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Reactant: CN1CCCC1=O
Reactant: CC(C)[SiH](C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc2c(c1)c([SiH](C)C)c(C(=O)Nc1ccc(N3CCC3)nc1)n2Cc1cccc(F)c1

Procedure:
Compound No. 21 was prepared according to a process similar to that described in stage 8.4, by reacting 0.15 g (0.31 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-bromo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 17.3, with 95 mg (0.93 mmol) of dimethyl(isopropyl)silane in the presence of 0.2 g (0.94 mmol) of potassium triphosphate and of 16 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP). 23 mg of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](=[N:27]/[OH:28])/[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(Cc1ccncc1)=N/O)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from (R)-4-(4-bromo-phenyl)-1-pyridin-4-yl-4-o-tolyl-butan-2-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=409.1 ([M+H]+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12]O)[C:6]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:5]=3[C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[BrH:24]>>[Br:24][CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:17][N:16]([CH3:18])[CH2:15][CH2:14][C:6]1=2
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CCO)C1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCBr)C1

Procedure:
A solution of 2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanol (0.2 g, 0.75 mmol) in aqueous HBr (2 mL) was heated at 120° C. for 15 h. The reaction was monitored by TLC and LCMS. The reaction mixture was basified with solid sodium bicarbonate, extracted with ethyl acetate. Organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by silica gel (100-200 mesh) chromatography followed by preparative TLC to obtain 5 mg of 5-(2-bromoethyl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a free base. The free base (0.005 g 0.0152 mmol) was further dissolved in 2 mL of THF, oxalic acid (0.001 g, 0.015 mmol) in THF (1 mL) was added to it and the resulting mixture was stirred for 30 min at room temperature. The precipitate obtained was filtered and dried under vacuum to afford 1.5 mg of 5-(2-bromoethyl)-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole as oxalate salt. 1H NMR (CD3OD) 7.55 (s, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 4.6 (t, 2H), 4.5 (s, 2H), 3.8 (t, 2H), 3.7-3.6 (m, 2H), 3.3 (bs, 2H), 3.1 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][C:16]([CH3:18])=[CH2:17])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7](C=O)[CH2:6][CH2:5]2.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.O>[CH3:17][C:16]1([CH3:18])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[NH:7][CH2:6][CH2:5]3)[CH2:15]1
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CCN2C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c3c1NCC3)CC(C)(C)O2
Yield: 45.7 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-6,7-dimethyl-4-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.23 g, 5.0 mmol) in methanol (4 mL) was added concentrated hydrochloric acid (2 mL)-methanol (1 mL) solution, and the mixture was heated to reflux for 2 hours under the nitrogen atmosphere. The reaction mixture was added to a mixture of sodium bicarbonate (3.02 g, 35.9 mmol) in water (10 mL)-ethyl acetate (10 mL) to neutralize, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, treated with active carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 497 mg of the title compound.
Reaction SMILES: COC(=O)C(C1C=CC(S)=C(OC)C=1)(C)C.[CH3:17][O:18][C:19](=[O:51])[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([S:30]CC3C=CC=C(OCC4C=CC(C(F)(F)F)=CC=4)C=3)=[CH:29][C:24]=2[O:23][C:22]1=[O:50]>>[CH3:17][O:18][C:19](=[O:51])[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([SH:30])=[CH:29][C:24]=2[O:23][C:22]1=[O:50]
Reactant: COC(=O)Cn1c(=O)oc2cc(SCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc21
Agent: COC(=O)C(C)(C)c1ccc(S)c(OC)c1
Product: COC(=O)Cn1c(=O)oc2cc(S)ccc21
Yield: 65 %

Procedure:
Compound 76C was prepared analogously to compound 21C using the product prepared from compound 76B. Yield was 65%. MS m/z 238 (M−1). Step 4. Preparation of {2-Oxo-6-[3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-benzooxazol-3-yl}-acetic acid methyl ester (Compound 76D)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:10][CH2:11][CH2:12][O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Oc1c(F)cccc1F
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1OCCBr
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
A suspension of 2,6-difluoro phenol (18 g, 0.385 mol), 1,2-dibromoethane (71.6 ml, 0.83 mol) and K2CO3 (47.86 g, 0.3463 mol) in dry acetonitrile (190 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 7% ethyl acetate in petroleum ether as eluent to give the title compound (20.8 g) as colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[O:15])[CH3:14])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:18][O:19][C:20](=O)[O:21]C>>[O:15]=[C:13]([C:9]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][N:10]=1)[CH2:14][C:20]([O:19][CH3:18])=[O:21]
Reactant: COC(=O)OC
Reactant: CC(=O)c1nccc(N2CCCCC2)n1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1nccc(N2CCCCC2)n1
Temperature: 90 °C
Yield: 52 %

Procedure:
To a stirred solution of 1-[4-(piperidin-1-yl)pyrimidin-2-yl]ethanone (Intermediate 52, 0.6 g, 2.92 mmol) in dimethylcarbonate (10 mL), sodium hydride (0.281 g, 11.7 mmol, 60%) was added portion wise at 0-5° C. over a period of 10 min. The reaction mixture was heated to 90° C. for 4 h. The reaction mixture was quenched by adding ice water. The aqueous layer pH was adjusted to neutral with dilute HCl, the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried and concentrated. The crude product was purified by column chromatography (75% ethylacetate & pet ether) to obtain methyl 3-oxo-3-[4-(piperidin-1-yl)pyrimidin-2-yl]propanoate 0.4 g (52%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([NH2:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[NH2:20]
Reactant: NC(=O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: NC(=O)C(Cc1ccccc1)NC(=O)C(Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-propionamide to give the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO.[Cl-].[NH4+]>[CH3:17][CH:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 8-bromo-2-[(1-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (493 mg) in dry MeOH (4.37 mL) was added sodium methoxide solution (0.722 mL, 30% wt. in MeOH) and the mixture was stirred at reflux for 6 h. A further portion of sodium methoxide solution (0.120 mL, 30% wt. in MeOH) was added and the reaction was continued for 90 mins. The reaction was cooled and concentrated in vacuo to give an orange residue. The residue was taken up in saturated ammonium chloride (25 mL) and washed with EtOAc (25 mL). The organics were separated and washed with water (15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange foam (313 mg).