Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 97 mg (0.21 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 3 mL diethylamine in 7 mL THF. Yield: 50 mg of a yellow powder. LC-MSD, m/z for C25H23BrN4O2 [M+H]+=491.0, 493.0; HPLC retention time: 2.9 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 87.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (202 mg, 0.32 mmol) prepared in Example 60a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield the title compound (135 mg, 88%) as a colorless solid.
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)C.[CH3:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[N:32]=[C:31]3[C:27]([N:28]=[C:29](Cl)[N:30]3[CH2:33][C:34]([F:37])([F:36])[F:35])=[C:26]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:25]=2)=[CH:20][N:19]=1>O>[CH2:14]([C@H:13]1[NH:4][CH2:1][CH2:10][N:11]([C:29]2[N:30]([CH2:33][C:34]([F:35])([F:37])[F:36])[C:31]3[C:27]([N:28]=2)=[C:26]([N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[N:25]=[C:24]([C:21]2[CH:22]=[N:23][C:18]([NH2:17])=[N:19][CH:20]=2)[N:32]=3)[CH2:12]1)[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCCC1=O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Solvent: O
Product: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 120 h

Procedure:
Diisopropylethylamine (1.91 ml, 10.98 mmol) was added to an N-methyl-2-pyrrolidone suspension (5 ml) of 2-(R)-ethylpiperazine-2-hydrochloride (751 mg) and 2-(2-aminopyrimidin-5-yl)-8-chloro-6-(morpholin-4-yl)-9-(2,2,2-trifluoroethyl)-9H-purine (506 mg, 1.22 mmol) and the resulting mixture was heated at 100° C. and stirred for 5 days. Water was added to the reaction mixture and the resulting mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform:methanol=97:3 to 90:10) to give the title compound (562 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH3:10])[CH2:3][NH:4][C:5]([NH:7][CH2:8][CH3:9])=O.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:8]([NH:7][C:5]1[O:11][C:2]([CH3:1])([CH3:10])[CH2:3][N:4]=1)[CH3:9]
Reactant: CCNC(=O)NCC(C)(C)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCNC1=NCC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of N-(2-methyl-2-hydroxypropyl)-N'-ethylurea (7.2 g, 45 mmol) in CH2Cl2 (100 mL) at 0° C. was added a solution of thionyl chloride (5.4 g, 45 mmol) in CH2Cl2 (20 mL). The mixture was warmed to ambient temperature. After 2 hours, the mixture was concentrated in vacuo, and the resulting solid triturated with boiling water. The mixture was cooled to ambient temperature and made basic by addition of saturated aqueous K2CO3. The mixture was extracted with methylene chloride, dried over K2CO3, and concentrated in vacuo to afford 3.2 g (50% yield) of 2-ethylamino-5,5-dimethyloxazoline; NMR (DMSO-d6 /TFA) 3.2 (s, 2), 3.0 (q, 2), 1.3 (s, 6), 1.0 (t, 3) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])[CH2:18][CH2:17]1)=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH2:13][C:14](=[O:15])[N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:32])[F:31])[CH2:20][CH2:21]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Reaction time: 3 h
Yield: 73.98 %

Procedure:
4-Methyl benzoyl chloride (44 mg, 0.03 ml, 1.8 mmol) was added to a stirred a cold (0° C.) solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above)(100 mg, 0.28 mmol) and triethylamine (72 mg, 0.1 ml, 0.71 mmol) in DCM (5 mL) and stirring continued at room temperature for 3 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 91 mg (73.98% yield 4-methyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 98.52%. 1H NMR (DMSO-d6): δ 8.54-8.42 (bs, 1H), 7.88-7.62 (m, 5H), 7.58-7.5 (bs, 1H), 7.3-7.22 (d, 2H), 4.2-4.1 (d, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (bs, 2H), 3.3-3.0 (bd, 2H), 2.3 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.N1C=CC=CC=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([NH:11][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Nc1nc2ccc(F)cn2c1-c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)Nc1nc2ccc(F)cn2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine (compound l, 0.075 g, 0.00033 mol) was dissolved in tetrahydrofuran (5.0 mL) and pyridine (29 uL, 0.00036 mol) was added. Rxn cooled to 0° C. and 4-fluorophenylacetyl chloride (48 uL, 0.00036 mol) was added. The reaction was stirred at 0° C. for 30 minutes. The solvent was removed and the crude product was partioned between water (25 mL) and EtOAc (25 mL). The layers were separated and the organic layer was washed 3×20 mL with water. The organic layer was dried (magnesium sulfate) then chromatographed on silica (70% ethyl acetate/hexanes) to give N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide Rf 0.37, 70% ethyl acetate/hexanes; MS m/z 364 (M+H). SH-SY5Y_EC50 (μM): 0.7321.
Reaction SMILES: CI.[C:3]1([CH2:9][O:10][C:11]([C:13]2([NH:19][C:20]([N:22]3[CH2:26][CH2:25][NH:24][C:23]3=[O:27])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:3]1([CH2:9][O:10][C:11]([C:13]2([NH:19][C:20]([N:22]3[CH2:26][CH2:25][N:24]([CH3:28])[C:23]3=[O:27])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)C1=O
Yield: 45.9 %

Procedure:
1.83 g (12.9 mmol) of methyl iodide was added to a solution of 1.50 g (4.3 mmol) of 1-[[(2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 1.78 g (12.9 mmol) of potassium carbonate in 100 ml of acetonitrile, and the mixture was heated under reflux overnight. The reaction solution was concentrated, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 710 mg (50%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.C[CH2:25][N:26]([CH:30]([CH3:32])C)[CH:27](C)C.BrC/C=[CH:36]/[C:37](Cl)=[O:38].[Cl-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([NH:19][C:37](=[O:38])[CH:36]=[CH:32][CH2:30][N:26]([CH3:25])[CH3:27])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)/C=C/CBr
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(C)C
Yield: 57.1 %

Procedure:
To a mixture of 1.9 g (5.1 mmol) of 4-[(3-bromophenyl)amino]-7-methoxy-6-amino-3-quinolinecarbonitrile and 5.3 ml (31 mmol) of Hunig's base in 110 ml of dry THF at 0° C., with stirring, was added a THF solution containing 5.7 g (31 mmol) of 4-bromo crotonyl chloride dropwise. The mixture was stirred for additional 0.5 hour after addition. 100 ml of saturated sodium chloride solution was added to the reaction mixture, then it was extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and then was added to 40 ml of dimethyl amine solution (2.0 M in THF) at 0° C. dropwise. The solution was stirred an additional 0.5 hour. The mixture was poured into diluted sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate. Chromatography gave 1.4 g of beige solid: mass spectrum (electrospray, m/e): M+H 480.0 and 481.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22](O)=[O:23])[C:11]3=[O:28])[CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:60]5[CH2:65][CH2:64][O:63][CH2:62][CH2:61]5)=[O:23])[CH:20]=4)[C:11]3=[O:28])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.3 %

Procedure:
A mixture of (1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoic acid (117 mg, 0.3 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)(145 mg, 0.45 mmol), N,N-Diisopropylethylamine (DIPEA) (154 μL, 0.9 mmol) and morpholine (79 μL, 0.9 mmol) in DMF (2 mL) was stirred at room temperature for 14 hours. Purification by preparative HPLC gave desired product as a white solid (83 mg, 60%). LC/MS m/e calcd. for C27H23ClN2O3: 458, observed (M+H)+: 459.2 1H NMR (400 MHz, MeOD-d4) δppm 2.23-2.31 (m, 2 H) 3.28-3.32 (m, 1 H) 3.77 (br. s., 8 H) 6.16 (d, J=7.58 Hz, 1 H) 6.81 (t, J=7.58 Hz, 1 H) 6.93 (d, J=7.83 Hz, 1 H) 7.11-7.19 (m, 1 H) 7.26-7.33 (m, 2 H) 7.33-7.38 (m, 2 H) 7.56 (d, J=7.58 Hz, 1 H) 7.60-7.67 (m, 2 H) 7.68-7.76 (m, 1 H).
Reaction SMILES: [CH2:1]([Li])CCC.I[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1C)[CH2:10][OH:11].C[O:17][B:18](OC)[O:19]C>>[OH:11][CH2:10][C:9]1[C:8]([CH3:1])=[C:7]([B:18]([OH:19])[OH:17])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(CO)cc1I
Reactant: [Li]CCCC
Reactant: COB(OC)OC
Product: Cc1c(CO)cccc1B(O)O
Yield: 27.1 %

Procedure:
Butyllithium (2.5 M, 4 mL, 10 mmol), 3-iodo-4-methyl-benzyl alcohol (1 g, 4 mmol), and trimethylborate (6 mL, 53 mmol) were reacted as in Example 5: step b. Aqueous workup and purification by SiO2 flash chromatography (40–50% EtOAc in hexanes) yielded the title compound (180 mg, 27%). The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): δ 7.06–7.30 (m, 3H), 4.56 (s, 3H), 4.16 (br s, 1H), 2.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:27]([CH2:30][NH2:31])[CH:28]=C.[CH3:32]N(C=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][N:31]([CH2:30][CH:27]=[CH2:28])[CH3:32])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCCN
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCCCCBr)ccc21
Reactant: CN(C)C=O
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Cl)cc1
Yield: 66 %

Procedure:
240 mg (0.55 mmol) 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester and 260 μl (2.7 mmol) N-allylmethylamine were stirred in 5 ml DMF at RT for 3 h. The mixture was extracted with ether and water, the organic phase was washed with water and dried over Na2SO4. Purification by column chromatography on silica gel with CH2Cl2/MeOH 9:1 yielded 154 mg (66%) 6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 429 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[CH3:32][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)c1
Yield: 73.6 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and meta-tolyl isocyanate (0.0095 mL, 0.076 mmol) were reacted to give the title compound as a pale tan solid (21.6 mg, 73%). 1H NMR (DMSO-d6) δ: 10.68 (br. s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 7.98 (dd, J=7.9, 1.2 Hz, 1H), 7.41-7.45 (m, 3H), 7.29 (s, 1H), 7.21-7.25 (m, 3H), 7.13-7.16 (m, 1H), 7.05-7.08 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.78 (d, J=7.3 Hz, 1H), 4.20-4.24 (m, 1H), 3.70-3.75 (m, 1H), 3.51-3.59 (m, 2H), 2.93-2.99 (m, 1H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([C:17]([O:19]CC)=[O:18])=[CH:15][N:16]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.O>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:23]1[CH:22]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[Cl:1])[CH:24]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=1)=[O:10]
Reactant: CCOC(=O)c1cnc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ncc(C(=O)O)s1)c1cc(OCc2ccccc2Cl)cc(OCc2ccccc2Cl)c1

Procedure:
A solution of ethyl 2-[3,5-di-(2-chlorobenzyloxy)benzoyl]aminothiazole-5-carboxylate (158 mg, 0.28 mmol) in THF (2 ml) was treated with sodium hydroxide solution (0.57 ml of 2M, 1.4 mmol), and the reaction stirred at 40-50 deg C., until complete hydrolysis was achieved (with tlc monitoring, approximate reaction time 2 hrs). The resulting solution was cooled, diluted with water (5 ml) and acidified to pH1 using c.HCl. The precipitate thus formed was filtered off, washed (water) and dried to give the title compound as a colourless solid, 130 mg, 1H NMR δ (d6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.2 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4cnc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Yield: 49.1 %

Procedure:
To a solution of ethyl 1-{2-[3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D112) (200 mg, 0.368 mmol) in Isopropanol (8 mL) and Water (8.00 mL) was added NaOH (3.68 mL, 1.841 mmol). The reaction was stirred at 90° C. for 2 hr before the isopropanol was removed in vacuo. The residue was acidified with aq HCl (2 M) until pH ˜2. The aqueous layer was extracted with ethyl acetate and the organic phases were dried and concentrated, purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E75) (93 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.28 (6H, d), 1.68 (2H, m), 2.05 (2H, m), 2.51 (1H, m), 2.73 (2H, m), 3.07 (4H, m), 3.23 (2H, m), 3.48 (1H, m), 3.64 (1H, m), 5.37 (1H, m), 7.30 (2H, m), 7.68 (1H, d), 8.47 (1H, d), 8.81 (1H, d), 9.54 (1H, s br). δF (DMSO-d6, 376 MHz): −73.6. MS (ES): C26H31ClN4O3S requires 514.2. found 515.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20](Cl)(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:27]>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20]([NH2:27])(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1C(=O)c1ccc(F)cc1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1

Procedure:
A solution of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonyl chloride (5.39 g, 14.2 mmol), [prepared as described in step 2 above], in dioxane (100 ml), was cooled in an ice bath under nitrogen, and concentrated ammonium hydroxide (20 ml) was added dropwise. After 1h, the dioxane was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution, 20-60% ethyl acetate/hexane) and then recrystallized from ethyl acetate/hexane to afford 2.7 g of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalene-sulfonamide as white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.O>O1CCCC1>[CH:11]1([CH2:14][NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1NCC1CC1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
3 g (18.9 mM) of 2-chloro-3-nitropyridine and 5 g (70.3 mM) of cyclopropylmethylamine in 12 ml of tetrahydrofurane were refluxed under stirring for 1 h. Water was added and the aqueous layer was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 3.5 g of N-(cyclopropylmethyl)-3-nitropyridin-2-amine as a yellow oil. Yield: 95%.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][C@H:13]2[CH2:16][C@H:15]([NH2:17])[CH2:14]2)=[CH:7][C:6]=1[F:18])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[N:28]1[CH:29]=[CH:30][N:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[C:32]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:4][C:2]([C:5]1[C:6]([F:18])=[CH:7][C:8]([O:12][C@H:13]2[CH2:14][C@H:15]([NH:17][CH2:37][C:33]3[C:32]4[N:31]([CH:30]=[CH:29][N:28]=4)[CH:36]=[CH:35][CH:34]=3)[CH2:16]2)=[CH:9][C:10]=1[F:11])([CH3:1])[CH3:3]
Reactant: O=Cc1cccn2ccnc12
Reactant: CC(C)(C)c1c(F)cc(O[C@H]2C[C@H](N)C2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1c(F)cc(O[C@H]2C[C@H](NCc3cccn4ccnc34)C2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of trans-3-{[4-(1,1-dimethylethyl)-3,5-difluorophenyl]oxy}cyclobutanamine (73 mg, 0.286 mmol) in anhydrous DCM (3 mL) was treated with DIPEA (0.06 mL, 0.343 mmol). A solution of imidazo[1,2-a]pyridine-8-carbaldehyde (41.8 mg, 0.286 mmol) in anhydrous DCM (3 mL) was added and the reaction was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (121 mg, 0.572 mmol) was added portionwise and the reaction was stirred at room temperature under nitrogen overnight. Water (10 mL) was added and the phases were separated. The organic layer was concentrated and the residue was purified by MDAP to give the title compound (79.4 mg).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:25][N:24]4[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C-:26]#[N:27].[Na+]>CN(C)C=O>[C:26]([C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:25][N:24]4[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1)#[N:27]
Reactant: [C-]#N
Reactant: Brc1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2

Procedure:
A stirred mixture of 3.96 g. (0.01 mole) of 3-(2-bromothioxanthen-9-ylidene)quinolizidine, 2.70 g. (0.015 mole) of cuprous cyanide, 50 mg. of cupric sulfate, 50 mg. of sodium cyanide in 40 ml. of dimethylformamide is heated at reflux temperature for eighteen hours. The cooled reaction mixture is then poured into 200 ml. of 1 M sodium cyanide. The resulting mixture is extracted with ether. After being washed with an aqueous solution of sodium cyanide and water, the ether solution is dried over magnesium sulfate. The dried solution is concentrated. The residual liquid is chromatographed on an alumina column using ether as the eluate. Evaporation of the appropriate fractional eluant gives 3-(2-cyanothioxanthen-9-ylidene)quinolizidine. A solution of the product in ethanol is treated with a molar equivalent of fumaric acid. The resulting crystals are recrystallized from ethanol to give 3-(2-cyanothioxanthen-9-ylidene)quinolizidine fumarate.