Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>[OH-].[Na+]>[C:7]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)c1ccccc1)C(=O)O

Procedure:
L-alanine (17.8 g., 0.2 mole) was dissolved in 2N-sodium hydroxide solution (120 ml.) with cooling to 0°-5° C. Benzoyl chloride (30.0 g., 0.22 mole), followed by 2N-sodium hydroxide (120 ml.), were then added to the solution in ten equal and alternate portions with vigorous intermittent shaking and ice cooling. The mixture was continually maintained at an alkaline pH. After completion of the addition, the mixture was shaken for 15 minutes at room-temperature. The clear solution obtained was acidified with concentrated hydrochloric acid to pH2 whilst ice cooling to give N-benzoyl L-alanine as a solid (27.8 g.), m.p. 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:34])[C:13]([N:21]3[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[C:14]([F:20])[C:15]=2F)[N:10]([CH:35]2[CH2:37][CH2:36]2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CS(C)=O>[C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:34])[C:13]([N:21]3[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]3)=[C:14]([F:20])[C:15]=2[NH:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:10]([CH:35]2[CH2:36][CH2:37]2)[C:9]1=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Yield: 86.8 %

Procedure:
A solution of {7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 8 (0.51 g, 0.914 mmol), triethylamine (1.3 mL, 9.3 mmol), and benzylamine (0.50 mL, 4.6 mmol) in dimethyl sulfoxide (7.5 mL) is heated at 100° C. for 16 hours in a sealed glass tube. The mixture is concentrated under high vacuum and the residue purified by column chromatography (1:2 ethyl acetate/hexanes) to afford {7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester as a solid (0.51 g). 1NMR (CDCl3): δ 8.50 (bs, 1H), 7.37–7.18 (m, 5H), 6.56 (bs, 1H), 4.76–4.62 (bd, 1H), 4.59–4.48 (m, 2H), 4.34–4.18 (m, 1H), 3.93–3.49 (m, 3H), 3.48–3.20 (m, 2H), 2.24–2.04 (m, 1H), 1.96–1.74 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 1.13–1.00 (m, 2H), 0.75–0.61 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10]Br>C(Cl)Cl>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1cccc(O)c1
Solvent: ClCCl
Product: O=Cc1cc(O)ccc1Br
Reaction time: 22 h
Yield: 63.7 %

Procedure:
To a suspension of 3-hydroxybenzaldehyde (1 kg, 8.2 mol) in CH2Cl2 (10 L) was added a solution of bromine (1.3 kg, 8.2 mol) in CH2Cl2 (620 mL) over 1 h. After stirring for about 22 h, the solids were isolated by filtration, washed with CH2Cl2 (4 L), and dried under vacuum to afford of 2-bromo-5-hydroxybenzaldehyde as a tan solid (1.05 kg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:28][C:29]1[CH:30]=[C:31]([S:36]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([C:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:43]=[C:42]3[NH2:67])(=[O:38])=[O:37])[CH:32]=[C:33]([F:35])[CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19](=[O:21])[NH:67][C:42]3[C:41]4[C:45](=[CH:46][CH:47]=[C:39]([S:36]([C:31]5[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=5)(=[O:38])=[O:37])[CH:40]=4)[N:44]([C:48]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:43]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)cn2)CC1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-(4-carboxy-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.677 mmol) in dry dichloromethane (6 mL), at 0° C., under argon, were added two drops of N,N-dimethylformamide and 62 microL of oxalyl chloride (1.05 eq). After 15 minutes the volatiles were removed under reduced pressure at room temperature. The crude acyl chloride thus obtained was dissolved under argon into dry tetrahydrofuran (5 mL), cooled to 0° C. and treated with a solution of 5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamine (300 mg, 0.85 eq) and triethylamine (0.28 mL, 3 eq) in dry tetrahydrofuran (7 mL). The mixture was allowed to warm to room temperature overnight then evaporated to dryness. The residue was dissolved into dichloromethane, washed with water and with a saturated solution of sodium hydrogenocarbonate, dried over sodium sulphate and evaporated to dryness to give the crude title compound that was used as such for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15]2)=[C:2]([NH:1][C:32]([C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[O:33])[CH:7]=1)=[O:9]
Reactant: COC(=O)C1CCN(c2ccc(C=O)cc2N)CC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2NC(=O)c2cc(C)on2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of methyl 1-(2-amino-4-formylphenyl)piperidine-4-carboxylate 59 (0.488 g, 1.9 mmol) in DCM (10 mL) at 0° C. was added pyridine (0.300 mL, 3.7 mmol) and 5-methylisoxazole-3-carbonyl chloride (0.185 g, 1.3 mmol). The reaction mixture was stirred at 0° C. for 30 min, additional acid chloride (88 mg) was added and stirring was continued at 0° C. After 30 min, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 50% EtOAc in hexanes) gave methyl 1-(4-formyl-2-(5-methylisoxazole-3-carboxamido)phenyl)piperidine-4-carboxylate 60 (0.268 g, 39% yield) as a pale yellow solid. Mass spectrum: calculated for C19H21N3O5 371.2. found 372.2 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][CH2:16]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:20]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N4CCC(CN5CCCC5)CC4)c3c2)cc(Cl)c1O
Yield: 71.4 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}ethanone (30 mg, 0.072 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (25.4 mg, 71%) as a yellow brown solid: 1H NMR (500 MHz, CD3OD) δ 8.80 (s, 1H), 8.29 (s, 1H), 8.03 (s, 2H), 7.30 (d, J=2.1 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 3.99 (s, 3H), 3.49 (d, J=12.9 Hz, 2H), 3.24-3.12 (m, 6H), 3.02 (d, J=5.5 Hz, 2H), 2.70 (s, 3H), 2.13-1.96 (m, 7H), 1.77-1.62 (m, 2H); ESI MS m/z 494 [C28H32ClN3O3+H]+; HPLC>99% (AUC), tR=10.45 min.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][C:9]([NH2:11])=O)=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2].N1C=CC=CC=1>O1CCOCC1>[CH2:1]([N:3]1[C:7]([CH2:8][C:9]#[N:11])=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1CC(N)=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCn1nc(C)cc1CC#N
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
2-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-acetamide (2.0 g, 11.96 mmol) was dissolved in dioxane (180 ml) followed by the addition of pyridine (1.89 g, 23.9 mmol). The resulting solution was cooled to 0° C. and TFM (2.76 g, 13.16 mmol) was added drop by drop. The suspension was then slowly warmed to rt and stirring was continued in total for 4 h. The volatiles were removed under reduced pressure, the residue was dissolved in DCM (150 ml), washed with water (2×100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. After flash-chromatography (silicagel; DCM/methanol=40/1), 1.58 g (88%) of (2-ethyl-5-methyl-2H-pyrazol-3-yl)-acetonitrile was obtained. LC-MS: tR=0.65 min; [M+H]+=150.18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[O:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[O:13])=S)[CH:5]=[CH:6][CH:7]=1.[CH:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.C(N(CC)CC)C>CC#N.CO>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:31][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[O:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[O:13])[CH2:25]1
Reactant: NC1CCCC(N)C1
Reactant: Cc1cc(C(=O)NC(=S)Nc2cccc(F)c2)c(C(F)(F)F)o1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: Cc1cc(C(=O)N=C(Nc2cccc(F)c2)NC2CCCC(N)C2)c(C(F)(F)F)o1
Temperature: 65 °C
Yield: 78.8 %

Procedure:
N-((3-Fluorophenyl)carbamothioyl)-5-methyl-2-(trifluoromethyl)furan-3-carboxamide (1.40 g, 4.05 mmol) and cyclohexane-1,3-diamine (1.38 g, 12.1 mmol) were combined in MeCN (20 mL). Triethylamine (0.818 g, 8.10 mmol), NaBiO3 (1.13 g, 4.05 mmol), and BiI3 (0.119 g, 0.203 mmol) were then added and the reaction was heated to 65° C. for 16 hours. When the reaction was complete, the solution was cooled and diluted with MeOH. Then, the resulting mixture was filtered through celite and the filtrate evaporated. The residue was re-dissolved in EtOAc and washed with water, brine, and dried over MgSO4. The organic solvent was then evaporated in vacuo to yield 1.36 g (79%) of the title compound. LCMS (ESI): calc.=426; obs. M+H=427.3 (2 overlapping peaks in ˜2:1 ratio).
Reaction SMILES: I[C:2]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:21]1[C:20]([CH3:24])=[CH:19][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3-c3cccnc3)c2cc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxyquinoline (compound 164) (59 mg), pyridine-3-boronic acid (33 mg), and tetrakistriphenylphosphine palladium (10 mg) were dissolved in N,N-dimethylformamide (4 ml), a 2 M aqueous potassium carbonate solution (0.5 ml) was added to the reaction system, and the mixture was stirred at 100° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (13 mg, yield 25%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:28]=[C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH3:49])=[C:35]([NH:37][C:38]([C:40]2[N:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]3=[N:42][CH:41]=2)=[O:39])[CH:36]=1)[NH2:30]>CN1C(=O)CCC1>[N:42]1[CH:41]=[C:40]([C:38]([NH:37][C:35]2[CH:36]=[C:31]([C:29]3[N:28]=[C:12]([CH:10]4[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]4)[O:14][N:30]=3)[CH:32]=[CH:33][C:34]=2[CH3:49])=[O:39])[N:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of Boc-azetidine-3-carboxylic acid (162 mg, 0.8 mmol) in anhydrous NMP (4 mL) was added CDI (131 mg, 0.8 mmol). The reaction was stirred for 2 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (250 mg, 0.8 mmol) was added and the reaction was stirred for 15 minutes, then heated via microwave at 120° C. for 15 minutes. The crude was purified by reverse phase HPLC to afford tert-butyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F13) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s 1H), 9.51 (d, J=6.8 Hz, 1H), 8.70 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.86 (dt, J=12, 2.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.31 (td, J=6.8, 0.8 Hz, 1H), 4.06-4.38 (m, 5H) 2.37 (s, 3H), 1.40 (s, 9H). MS m/z 476.2 (M+1)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31]C4CCCCO4)=[CH:27][CH:26]=3)[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.Cl>C(O)C>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)[C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:30][CH:29]=1
Reactant: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: O=C(C1CCCCC1)N(Cc1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
A mixture of cyclohexanecarboxylic acid [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amide (1.64 g, 3.24 mmol), pyridinium p-toluenesulfonate (85 mg, 0.32 mmmol) and ethanol (30 mL) was stirred at room temperature for 24 hr. Aqueous 1N HCl (10 mL) was added and the reaction was stirred for 3–4 hr. The reaction mixture was concentrated to 1/3 the volume and saturated aqueous sodium bicarbonate was added. The aqueous solution was washed with methylene chloride and the organic solution was dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (3% methanol in methylene chloride to 15% methanol in methylene chloride) provided the title compound as a white solid (1.16 g). The solid was suspended in methanol (15 mL) and 1.4 mL of 4N HCl in dioxane was added dropwise. The reaction was stirred at room temperature for 0.5 hr. and was concentrated to provide the title compound as the hydrochloride salt. MS 423.2 (M+1)+
Reaction SMILES: C(=O)=O.[CH:4](O)([CH3:6])[CH3:5].[Li].BrC(C)=C.[CH3:13][C:14]1[CH:19]=[CH:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=1[CH:22]=[O:23].[Cl-].[NH4+]>C(OCC)C>[CH3:13][C:14]1[CH:19]=[CH:18][CH2:17][C:16]([CH3:20])([CH3:21])[C:15]=1[CH:22]([C:4]([CH3:6])=[CH2:5])[OH:23]
Reactant: CC1=C(C=O)C(C)(C)CC=C1
Reactant: CC(C)O
Agent: C=C(C)Br
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(C)C(O)C1=C(C)C=CCC1(C)C
Temperature: -10 °C
Reaction time: 2.5 h

Procedure:
Into a 500 ml reaction flask equipped with immersion thermometer, mechanical stirrer, 250 ml addition funnel, Friedrich's condenser, dry ice/isopropyl alcohol bath and gas bubbler is placed 1.9 grams (44.7 cm length) (0.28 gram atoms) of Li wire (cut up) and 100 ml anhydrous diethyl ether. The lithium wire/diethyl ether mixture is cooled with stirring to -10° C. 15.7 Grams (0.13 moles) of 2-bromo-1-propene (dissolved in approximately 40 ml anhydrous diethyl ether) is added dropwise from the addition funnel into the reaction mixture while maintaining the temperature thereof between -10° C. and -5° C. Following addition of the 2-bromo-1-propene, the reaction mass is stirred for a period of 30 minutes while maintaining the reaction mass at a temperature of 0° C. and is then stirred for 1.5 hours at room temperature (20° C.). The reaction mass is then chilled to -20° C. and 15.0 grams (0.10 moles) of Safranal is added dropwise while maintaining the reaction mass at from -20° up to -15° C. Following the addition of the Safranal, the reaction mass is stirred at -20° C. for a period of 15 minutes and then at room temperature for a period of 2.5 hours. The reaction mass is monitored on GLC at 30 minutes, 90 minutes and 150 minutes, at which point the reaction mass is poured into 300 ml of saturated ammonium chloride (aqueous). The reaction mixture is then added to 200 ml of anhydrous diethyl ether. The reaction mass is then washed with saturated aqueous sodium chloride, dried and concentrated yielding 18.67 grams of crude product. 1.0 Grams of crude product is set aside for silica gel chromatography. The remaining 17.56 grams is vacuum distilled yielding the following fractions:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[C:3]([NH:23][C:25]2[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1N
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1Nc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A mixture of intermediate 38 (0.10 g, 0.32 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170° C. for 25 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid triturated in a mixture of EtOAc/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a white solid (11 mg, 7%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19]Br)=[CH:13][N:12]=1>CN(C=O)C>[Br:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][N:3]2[CH2:8][CH2:7][S:6][CH2:5][C:4]2=[O:9])=[CH:15][CH:16]=1
Reactant: O=C1CSCCN1
Reactant: BrCCCc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSCCN1CCCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60.2 mg (1.38 mmol) of sodium hydride (55% suspension in mineral oil) were added to 161.7 mg (1.38 mmol) of thiomorpholin-3-one in 5 ml of DMF, and the mixture was stirred at room temperature for 15 min. Subsequently, 350 mg (1.25 mmol) of 2-bromo-5-(3-bromopropyl)pyridine were added. The reaction mixture was stirred for 3.5 h, concentrated, admixed with water and extracted with ethyl acetate. The organic phase was separated and concentrated. Yield: 421 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:9][NH2:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1

Procedure:
A solution of the crude phthalimide and hydrazine hydrate (10.0 ml, 177 mmol) in EtOH (200 ml) was stirred at reflux for 1 hour. Once cooled, the mixture was concentrated under reduced pressure. The residue was suspended in 1.5M HCl (200 ml) and washed with CH2Cl2 (50 ml×3). The organic solution was extracted with 4M HCl (50 ml×2). The combined aqueous extracts were made basic with 10M NaOH (100 ml) and extracted with CH2Cl2 (50 ml×4). This organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification gave ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester as an off-white solid (2.41 g, 51% over 2 steps).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[CH3:20][O:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[O:21][CH3:20])[CH2:27]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 81 (15% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.86 and 3.12 (2t, 2H), 3.54 and 4.16 (2t, 2H), 3.81-3.90 (m, 6H), 4.43 and 5.05 (2s, 2H), 6.51 and 6.90 (2d, 1H), 6.71 and 7.01 (2d, 1H), 7.63-7.68 (m, 1H), 7.94-8.04 (m, 2H), 8.28-8.31 (m, 1H), 8.53-8.57 (2s, 1H), 9.02-9.03 (2s, 1H); MS (ESI) m/z 433 ([M+H]+).