Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@H:20](OS(C)(=O)=O)[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([CH2:39][CH3:40])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:52][C:53]([CH3:59])([CH3:58])[CH2:54][CH2:55][CH2:56][SH:57].O>CC#N>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([S:57][CH2:56][CH2:55][CH2:54][C:53]([OH:52])([CH3:59])[CH3:58])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([CH2:39][CH3:40])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCCS
Reactant: CC[C@@H](C(=O)OCC[Si](C)(C)C)c1ccccc1CC[C@@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](C(=O)OCC[Si](C)(C)C)c1ccccc1CC[C@H](SCCCC(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
A suspension of mesylate of Step 6 (4.4 g, 66 mmol) and Cs2CO3 (4.3 g, 132 mmol) in CH3CN (44 mL) was degassed and then purged with N2. The suspension was then cooled to 0° C. and 4-hydroxy-4-methyl-1-pentanethiol (Step 7, 1.8 mL, 132 mmol) was added. The reaction was stirred for 30 min at 0° C. followed by 3 h at r.t. Water (50 mL) was then added and the product was extracted with EtOAc. The organic layer was washed with H2O and saturated NaCl solution. The solvent was removed under vacuum and the crude product was purified by flash chromatography (1:20 and 1:10 EtOAc:toluene) to give the title compound as an off-white foam (4.25 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].C1(/C=C/CC(Cl)=O)C=CC=CC=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: O=C(Cl)C/C=C/c1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)C/C=C/c1ccccc1
Yield: 55 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (E)-4-phenylbut-3-enoyl chloride (0.198 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.114 g, 1.19 mmol) and triethylamine (0.239 g, 2.37 mmol) in dichloromethane (5 mL) to give (E)-N-(2-azidoethyl)-4-phenylbut-3-enamide (0.168 g, 55% yield). 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J=15.6 Hz, 1H), δ 7.45 (d, J=3.3 Hz, 2H), δ 7.29 (m, 3H), δ 7.04 (t, J=4.1 Hz, 1H), δ 6.59 (d, J=15.9 Hz, 1H), δ 3.55 (q, J=6.0, 5.1 Hz, 2H), δ 3.47 (t, J=1.5 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 141.6, 134.9, 130.1, 129.1, 128.1, 120.8, 51.1, 39.4 ppm; HRMS (ESI) calcd for C11H12N4O (M+) 216.1011. found 216.1005.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([C:12]#[C:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[CH:10][N:11]=1)[CH3:2].C(N(CC)CC)C>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[CH:10][N:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Yield: 75.5 %

Procedure:
tert-Butyl 4-(4-((4-((3-(2-ethoxy-2-oxoethyl)pyrazin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I102) (I87 mg, 0.306 mmol) was dissolved in DMF (20 mL), triethylamine (0.1 mL) and a slurry of 10% Pd/C (0.100 g) in DMF (2 mL) was added. The mixture was purged with 3×vacuum/hydrogen cycles, and then stirred vigorously under a hydrogen atmosphere. After 17 hours the mixture was filtered through celite, and the celite washed with ethyl acetate (200 mL). The combined filtrates were washed with 1:1 water:saturated brine (4×100 mL), dried (sodium sulphate) and evaporated to give the title compound (I103) (142 mg, 76%) as a yellow oil; 1H NMR (400 MHz, d4-MeOD) δ 8.51 (d, J=0.6 Hz, 1H), 8.42 (d, J=2.6 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.20-7.13 (m, 2H), 4.21 (dd, J=11.4, 1.8 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.97 (s, 2H), 3.37 (s, 4H), 2.87 (br s), 2.70 (tt, J=11.9, 3.3 Hz, 1H), 1.83 (d, J=12.4 Hz, 2H), 1.59 (ddd, J=25.6, 12.9, 4.4 Hz, 2H), 1.48 (s, 9H), 1.21 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.76 min; m/z 615.1 [M+H]+, 559.1 [M−tBu+2H]+, 515.1 [M−Boc+2H]+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:35])([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)[CH:23]([F:25])[F:24]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][C:22]([F:21])([F:35])[CH:23]([F:24])[F:25])[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)(F)C(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 441.98 g/mol.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO>[CH:1]1([C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Solvent: CCO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1C1CCCCC1
Yield: 37.1 %

Procedure:
Trans-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (212 mg, 0.69 mmol) was subjected to chiral preparative HPLC (Column: Chiralcel OJ (250×20), 5 μm particle size, mobile phase: EtOH, flow rate 12 mL/min) to yield (2S,4S)-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (79 mg, 37%), Chiral purity 99.3% ee. Optical rotation [α]D20=+5.1 (acetonitrile, c=1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][NH2:12]>C1COCC1.CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:12][CH3:11])=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 3 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in anhydrous THF (100 mL) at 0° C. was added dropwise a solution of MeNH2 in EtOH. The resulting mixture was stirred at 3° C. for 4 h. The reaction mixture was concentrated under reduced pressure to yield a solid, which was suspended in EtOAc and filtered. The filtrate was washed with brine (2×100 mL), dried and concentrated to yield 4-chloro-N-methylpicolinamide (16.4 g, 60% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.55 (d, J=5.2 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.66 (m, 1H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 171.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]#[N:25])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][C@H:17]4[CH3:23])[C:5]=3[C:4]=2[CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]#[N:25])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][C@H:17]4[CH3:23])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C[C@@H]1CC(=O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 8-fluoro-1-{[(1R,2R)-2-methyl-4-oxocyclohexyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (7.23 g, 21.5 mmol) in MeOH (100 mL) was added sodium borohydride (1.63 g, 43.0 mmol) at 0° C. The reaction mixture was left to stir at room temperature for 1 h, treated with aqueous ammonium chloride and brine, and extracted with EtOAc. The combined organics were dried (sodium sulfate), and concentrated. The diastereomers were separated by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C19H19FN4O) [M+H]+, 339.2. found 339.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)c(Br)cn1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of 4-chloro-2-pyridylamine (6.0 g, 46.7 mmol) in chloroform (180 mL) was added N-bromosuccinimide (8.3 g, 46.7 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH2Cl2 (800 mL) and 1N NaOH (100 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (25-35% EtOAc/hexanes) yielding 3.63 g (38%) of 5-bromo-4-chloro-2-pyridylamine. LCMS (m/z): 206.9/208.9 (MH+). 1H NMR (CDCl3): δ 8.18 (s, 1H), 6.62 (s, 1H), 4.52 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([F:12])[C:9]([CH:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)O)=[CH:8][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:13][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[C:10]([F:12])[N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(NCc3ccccc3Cl)nc2F)c2cccnc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1nc(NCc2ccccc2Cl)ccc1Cc1c[nH]c2ncccc12

Procedure:
To [6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (606, 180.0 mg, 0.33 mmol) in acetonitrile (15.0 mL) were added triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.50 mL, 6.50 mmol). The reaction was heated to reflux for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0335, 24.9 mg, 19.4%). MS (ESI) [M+H+]+=367.0.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([O:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.NN.Cl>C(O)C>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([O:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][NH2:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/COc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Product: NC/C=C/COc1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A solution of 26.2 g of (E)2-[4-[4-(1H-imidazol-1-yl)phenoxy]-2-buten-1-yl]-1H-isoindole-1,3(2H)-dione (Example 30) in 1 liter of ethanol is treated with 5 ml of anhydrous hydrazine, and the mixture stirred at reflux for 18 hours. To the reaction mixture is added 25 ml of concentrated HCl and the mixture cooled to room temperature. The precipitate is collected and washed with 2 portions of 300 ml of water. The filtrate and aqueous washes are combined and taken to dryness in vacuo. The solid is treated with 25 ml of 10N NaOH, the mixture saturated with solid K2CO3, and then extracted with 500 ml of dichloro-methane. Removal of the dichloromethane in vacuo leaves a viscous oil that solidifies at room temperature. A portion is purified by recrystallization from hexane, and dried; m.p. 81°-83° C.; yield, 0.5 g.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CS(C)=O>>[N:33]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4([C:17]([N:19]5[CH2:23][CH2:22][C@@:21]6([C:27]7[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=7[C:25](=[O:32])[O:24]6)[CH2:20]5)=[O:18])[CH2:16][CH2:15]4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(F)nc5)cc4)CC3)C2)c2ccccc21
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(N6CCCC6)nc5)cc4)CC3)C2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of (1R)-1′-({1-[4-(6-fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20.0 mg, 0.0000467 mol, example 250), pyrrolidine (7.8 μL, 0.000093 mol) in dimethyl sulfoxide (0.5 mL, 0.007 mol) was heated at 100° C. in a sealed tube for 5 hours. The product was purified by prep-HPLC. LC-MS: 480.2 (M+H+)
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:35]=1[C:36]([NH:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4])=[O:37]
Reactant: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 23.38 g of methyl 2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 33 (0.2 TFA salt) in CH2Cl2 (50 ml) are added, at 0° C., triethylamine (22 ml) and 2,6-dichlorobenzoyl chloride (6.22 ml) dissolved in CH2Cl2 (6 ml). The reaction is stirred at RT for 2 h. The organic phase is washed with water, dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using CH2Cl2/Hexane 95/5 as eluent.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH3:23]I.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH3:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: CI
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and methyl iodide with sodium hydride in dimethylformamide there is obtained 1-(4-bromo-2-fluoro-5-methoxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 175°-177° C.;
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C([N:11]1[CH2:16][C:15]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:25][C:24]=3[F:32])[CH2:18][CH2:17]2)[O:14][CH2:13][CH2:12]1)=O>O.C(#N)C>[O:14]1[C:15]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:25][C:24]=3[F:32])[CH2:18][CH2:17]2)[CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(N1CCOC2(CCN(Cc3cc(CCO)ccc3F)CC2)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: OCCc1ccc(F)c(CN2CCC3(CC2)CNCCO3)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of sodium carbonate (1.4 g) in water (40 mL) was added to a solution of 2,2,2-trifluoro-1-(9-(2-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone [Example 44, step b] (4.2 g) in acetonitrile (40 mL). The reaction mixture was stirred at 20° C. for 20 hours. The acetonitrile was removed under reduced pressure and the remaining aqueous solution was extracted with DCM (×9). The combined DCM extracts were dried, filtered and the solvent removed under reduced pressure to yield the subtitled compound. Yield 2.7 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=S)[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1.[OH2:29].CI>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:29])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1
Reactant: O
Reactant: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=S)cc(C(=O)OCC)oc12
Solvent: CC(C)=O
Solvent: CI
Product: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 6-chloro-8-methoxycarbonyl-10-propyl-4-thioxo-4H-pyrano[3,2-g]quinoline-2-carboxylate (0.030 g) in acetone (10 ml) containing water (0.2 ml) and methyliodide (0.1 ml) was stirred in the dark at room temperature for 2 days. Concentration of the reaction mixture gave a light buff solid, which was recrystallised from ethanol to give the title compound (0.015 g), mp 176°-179°.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][C:18](N)=S.CS(C)=O>CCCCCC.CCOC(C)=O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][C:14]([CH3:16])=[CH:13][CH:12]=3)[N:1]=[CH:18][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: NC(N)=S
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(-c3ccccc3)ncnc2c1
Temperature: 140 °C
Yield: 98.9 %

Procedure:
To a 20 mL microwave reaction vial with a micro magnetic stir bar, were added 0.284 g of 2-amino-4-methylbenzophenone, 0.208 g of thiourea and 3 mL of DMSO. Then the vial was sealed and heated with microwave at 140° C. for 20 hours to form an orange liquid. The reaction mixture was treated in a similar method via column chromatography with hexane/EtOAc (6:1) as eluent to afford 0.293 g of 4-phenyl-7-methyl-quinazoline, in a yield of 99.0%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][NH2:19].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CN1C(=O)CCC1>[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:19][CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:20])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])[CH:26]=1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3cccc(CC(=O)OC)c3)c2n1
Reaction time: 0.25 h

Procedure:
The product from step (ii) (3.1 g) and methyl(3-formylphenyl)acetate (1.6 g) were dissolved in NMP (30 ml) and stirred for 15 min. Sodium triacetoxyborohydride (3.7 g) was added and the mixture stirred at rt for 20 h. After addition of methanol (1 ml), the mixture was purified by SCX, which afforded the subtitle compound. Yield 3.1 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:11][C:10]1[NH:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=2)=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)[nH]c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Temperature: 100 °C
Reaction time: 17 h
Yield: 82.9 %

Procedure:
To 11.0 g of 5-methyl-2-(4-trifluoromethoxy-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester in 40 ml of ethanol was added 40 ml of a 2N—NaOH solution and the reaction mixture was stirred at 100° C. for 17 hours. After such time the reaction mixture was cooled to +5° C. and treated with 80 ml of a 1N HCl solution. The precipitate was filtered, washed with water and dried under high vacuo to yield 8.3 g of a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[NH2:8][C:7]1[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[N:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=1
Reactant: Nc1cc(N2CCOCC2)cnc1Cl
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ncc(N3CCOCC3)cc2N)cc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
2-Chloro-5-morpholinopyridin-3-amine (0.25 g, 1.2 mmol), 4-cyanophenylboronic acid (0.21 g, 1.4 mmol), tricyclohexylphosphine (39.4 mg, 0.14 mmol), and tris(dibenzylideneacetone)dipalladium (0) (64.8 g, 0.07 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (3.0 mL) and aq. 1.3M potassium phosphate tribasic (2.7 mL, 3.5 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-30% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a light yellow solid as 4-(3-amino-5-morpholinopyridin-2-yl)benzonitrile. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.91 (5H, m), 6.67 (1H, d, J=2.4 Hz), 5.19 (2H, s), 3.82 (4H, m), 3.21 (4H, m). Mass Spectrum (pos.) m/e: 281.0 (M+1).