Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[O:4][N:3]=1.[H-].[Na+].Br[CH2:15][CH2:16]Br.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:8]([O:10][CH3:11])=[O:9])[CH2:16][CH2:15]2)[O:4][N:3]=1
Reactant: COC(=O)Cc1cc(C)no1
Reactant: BrCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 15 mL round bottom flask was added methyl 2-(3-methylisoxazol-5-yl)acetate (250 mg, 1.61 mmol) dissolved in N,N-dimethylformamide (7 mL) followed by addition of sodium hydride (60% suspension in mineral oil, 322 mg, 8.06 mmol). The mixture was stirred at room temperature for 15 minutes. 1,2-Dibromoethane (417 μL, 4.83 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. A saturated aqueous solution of sodium bicarbonate was added to the mixture and it was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.5 mL) and washed (3×) with an aqueous (10%) lithium chloride solution to remove residues of N,N-dimethylformamide. The organics were dried over sodium sulfate, decanted and concentrated under reduced pressure to afford methyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate MS (ES+) (M+H) 182.0; LCMS retention time: 2.53 minutes (Method L). The material was used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:21][CH3:22])[NH:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[C:18]([S:21]([CH3:22])=[O:31])[NH:19][CH:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Yield: 38.7 %

Procedure:
To a solution of 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthioimidazole in 5 ml of chloroform was added 0.18 g of m-chloroperbenzoic acid at room temperature and the mixture was stirred for a day. The reaction mixture was washed with a diluted alkali solution, dried, concentrated under reduced pressure, and the residue thus formed was recrystallized from cyclohexane to provide 0.13 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylimidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 8 h
Yield: 76.6 %

Procedure:
tert-Butyl [4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (39.92 g, 85.57 mmol) was dissolved in toluene (1700 mL) and added to a Parr vessel charged with 5% platinum on carbon (3.9 g) and a small volume of toluene. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa). The hydrogen was replaced three times, and the reaction was shaken overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol (700 mL). The filtrate was concentrated under reduced pressure to provide 28.62 g of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate as a brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]2[N:16]=[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28][C:22]=4[CH:21]=3)[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][CH2:39][S:40]([CH3:43])(=[O:42])=[O:41].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:43][S:40]([CH2:39][CH2:38][N:26]1[CH2:27][CH2:28][C:22]2[CH:21]=[C:20]([NH:19][C:17]3[N:18]=[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH2:3][O:2][CH3:1])[N:15]4[N:16]=3)[CH:30]=[CH:29][C:23]=2[CH2:24][CH2:25]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)CCCl
Reactant: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCNCC4)nn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCN(CCS(C)(=O)=O)CC4)nn12
Temperature: 60 °C
Yield: 49 %

Procedure:
To a solution of [5-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.100 g, 0.250 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.103 g, 0.751 mmol), 1-chloro-2-methanesulfonyl-ethane (0.053545 g, 0.37548 mmol), followed by sodium iodide (0.037 g, 0.250 mmol) and the reaction was heated at 60° C. overnight then cooled to room temperature. The reaction was diluted with ethyl acetate, washed with water several times, washed with brine, dried over sodium sulfate, and concentrated. Product was isolated as a pale yellow foam (0.062 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.64 (d, J=7.7 Hz, 1H), 7.59-7.42 (m, 5H), 7.31-7.29 (m, 1H), 7.24-7.20 (m, 1H), 7.08 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.92-6.88 (m, 1H), 4.35 (br s, 2H), 3.20-3.14 (m, 5H), 3.06 (s, 3H), 3.01 (t, J=6.1 Hz, 2H), 2.87-2.82 (m, 4H), 2.71-2.64 (m, 4H). MS=506 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1>C(OC(OCC)(OCC)C)C>[F:20][C:19]1[C:2]2[N:1]=[C:23]([CH3:24])[O:22][C:3]=2[C:4]2[NH:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:5]=2[C:18]=1[F:21]
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(I)cc2F)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)(OCC)OCC
Product: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(I)cc3F)c2o1
Yield: 535.7 %

Procedure:
Intermediate I-18a was prepared from 5-amino-6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-13a: 550 mg, 1.3 mmol) in 1,1,1-triethoxy-ethane (5 mL) and p-toluene sulfonic acid (20 mg, 0.13 mmol) using procedures analogous to those described above for Intermediate I-16a to afford 310 mg of the product (53.6% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.39 (s, 1H), 7.96 (dd, 1H), 7.78 (d, 1H), 7.48 (t, 1H), 2.67 (s, 3H). LCMS: 92.6%, m/z=445.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5](=[O:13])[CH:4]=[CH:3]1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5](=[O:13])[C:4]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:3]1
Reactant: Cc1ccc2c(=O)ccn(C)c2c1
Reactant: O=S(=O)(O)Cl
Product: Cc1ccc2c(=O)c(S(=O)(=O)Cl)cn(C)c2c1
Temperature: 25 °C

Procedure:
1,7-Dimethyl-4-quinolone (4.31 g) was stirred with chlorosulphonic acid (11.95 ml) at 140° for 2.5 hours and then cooled to room temperature and poured carefully into ice water (1 liter). The resulting white solid was collected, washed with water and dried to give the novel compound 1,7-dimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride, m.p. >300°.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@@H:17]([OH:33])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:54](O)=[O:55].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@H:17]([O:33][CH:54]=[O:55])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@@H](O)CC[C@]3(C)[C@H]21
Reactant: O=CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](OC=O)CC[C@]3(C)[C@H]21

Procedure:
11β-N,N-Dipropylaminoacetoxy-3β-hydroxy-5α-pregnan-20-one (110 mg) was stirred with triphenylphosphine (364 mg) and formic acid (0.1 ml) in tetrahydrofuran (5 ml.) and diethylazodicarboxylate (240 mg) added. Further reagent (5 drops) was added until a good yellow colour persisted. After 16 hours the mixture was concentrated and filtered through silica gel (20 g) in ethyl acetate: petroleum ether (1:1). Evaporation of the eluate gave a residue which was purified by preparative TLC (ethyl acetate: petroleum ether (1:1)) to give 11β-N,N-dipropylaminoacetoxy-3α-formyloxy-5α-pregnan-20-one (30 mg), [α]D +73°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Cl)[CH:18]=1.C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:18]=1
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Reactant: Clc1cncc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2cncc(Cl)c2)c1
Temperature: 135 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A mixture of 3-nitrostyrene (3.98 g), 3,5-dichloropyridine (3.70 g), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (7.0 g) and sodium bicarbonate (5.3 g) in N,N-dimethylformamide (35 ml) was stirred at 135° C. for 2 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-chloro-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (3.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:21].Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])=[N:28][C:23]([NH:21][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:24][CH:25]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(N1CCN(C)CC1)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CCC(N1CCN(C)CC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-(4-methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was prepared in an analogous manner to Example 179. Product was isolated as a single diastereomer (21.7 mg, 7%). LCMS (m/e) 552 (M+H); 1H NMR (CDCl3, 400 MHz) δ 11.74 (s, 1H), 9.13 (d, 1H, J=8.08 Hz), 7.71 (s, 1H), 7.62 (d, 1H, J=8.34), 6.90 (d, 1H, J=8.34 Hz), 6.30 (m, 1H), 6.10 (m, 1H), 5.91 (s, 1H), 5.53 (s, 1H), 4.00 (t, 1H, J=7.32 Hz), 3.72 (s, 3H), 3.42-3.58 (m, 8H), 3.08 (s, 1H), 2.90 (m, 1H), 2.88 (s, 1H), 2.83 (s, 3H), 2.75 (m, 2H), 2.35-2.45 (m, 6H), 2.10 (d, 1H, J=10 Hz), 1.59 (d, 1H, J=8.33 Hz), 1.49 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH:21]([F:23])[F:22])C1C=CC=CC=1.[H][H]>[Pd].CO.[OH-].[OH-].[Pd+2]>[F:23][CH:21]([F:22])[CH:9]1[NH:8][CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C(F)F)C1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC(C(F)F)C1
Yield: 97.1 %

Procedure:
10% Palladium on carbon (65 mg, 0.061 mmol) was added to a solution of tert-butyl 4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (0.20 g, 0.61 mmol, racemic from Step 3) in methanol (15 mL). The suspension was stirred under an atmosphere of hydrogen provided by a balloon. When the reaction showed no progress, 20% Pd(OH)2 on charcoal (47 mg, 0.061 mmol) was added and the suspension was shaken under 50-55 psi hydrogen for 2 h. The mixture was filtered and solvent removed in vacuo to afford product as a viscous oil (140 mg, 97%). 1H NMR (300 MHz, CDCl3): δ 5.90 (td, 0.1H), 5.52-5.12 (br s, 2H), 4.25-3.96 (br s, 1H), 3.94 (d, 1H), 3.27-2.77 (m, 4H), 1.45 (s, 9H); LCMS (M-tBu+2H)+: 181.0.
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[IH:19].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[I:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:18]
Reactant: O=C1CCCCCCCCCCCCCCCO1
Reactant: I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCI
Temperature: 100 °C

Procedure:
16-Hexadecanolide (5.0 g, 0.02 mol) was added to a mixture of HI (30 g) and acetic acid (20 g). The mixture was heated to 100° C. overnight. After cooling it was poured into a cold sodium thiosulphate solution (150 mL, 10%) and extracted using CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated to give a white solid. The crude product was recrystallised from diethyl ether. Yield: 4.8 g (64%)
Reaction SMILES: [C:1]([C:3](=[C:9]([S:17][CH3:18])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6]CC)=O)#[N:2].[CH3:19][N:20]=[C:21]=[O:22]>>[C:1]([C:3]1[C:4](=[O:6])[N:20]([CH3:19])[C:21](=[O:22])[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]=1[S:17][CH3:18])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(Nc1ccccc1)SC
Reactant: CN=C=O
Product: CSc1c(C#N)c(=O)n(C)c(=O)n1-c1ccccc1
Yield: 27 %

Procedure:
This compound was synthesized from ethyl 2-cyano-3-methylthio-3-phenylaminoacrylate and methyl isocyanate according to the same process as described in Example 92b. Yield=27%.
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O>C(N(CC)CC)C>[OH:4][C:5]1[C:10]([C:11]([Cl:1])=[O:13])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cnccc1O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1cnccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 80 ml. of dichloromethane solution containing 9.8 g. of 4-hydroxynicotinic acid and 10 ml. of triethylamine was added dropwise 7 ml. of thionyl chloride with stirring under ice-cooling over a period of 20 minutes and the mixture was stirred for 2 hours at room temperature. The crystals thus formed were recovered by filtration, washed with a small amount of dichloromethane, and then dried to provide 4-hydroxynicotinoyl chloride.
Reaction SMILES: CC1O[C:4]2([N:25]3[CH2:30][CH2:29]OC[CH2:26]3)[CH:9]([CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[C:11]=1[N+:12]([O-:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]2.[Cl-].C[NH3+]>C(O)C>[CH3:26][N:25]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:23])[F:24])[C:11]([N+:12]([O-:14])=[O:13])=[C:30]1[CH3:29]
Reactant: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2CCCCC2(N2CCOCC2)O1
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CCO
Product: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2=C(CCCC2)N1C

Procedure:
2 g (4.7 mmol) of 2-methyl-8a-morpholino-3-nitro-4-(2-trifluoromethylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene are heated at the reflux temperature in 15 ml of ethanol with 2 g of methylammonium chloride for 6 hours. After cooling, the salts are filtered off with suction, the solution is evaporated, the residue is taken up in chloroform and the mixture is washed with water. The organic phase is dried and concentrated and the residue is chromatographed on silica gel with chloroform with 1% of methanol. Intensely yellow crystals are obtained from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([N:31]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]#[CH:38])[C:32]1=[O:39])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([N:31]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]#[C:38][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])[C:32]1=[O:39])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CCN1CCN(C(C)(C)C)C1=O
Product: CC(C)(C)N1CCN(CC#Cc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)C1=O
Yield: 83.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with 1-tert-butyl-3-prop-2-ynyl-imidazolidin-2-one (360 mg, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (19:1 to 3:2 gradient) to give 6-[3-(3-tert-butyl-2-oxo-imidazolidin-1-yl)-prop-1-ynyl]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 83%) as a yellow oil. LC-MS (ES+) m/z: 478 (M+Na)+, 456 (M+H)+, tR=4.43 min.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=1.CCN(CC)CC>CC#N>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:1][CH3:2])[N:12]=[C:11]([NH2:16])[N:10]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@@H]1CCCN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of (2R)-2-ethylpyrrolidine (80 mg, 0.59 mmol), 4,6-dichloro-2-pyrimidinamine (119 mg, 0.726 mmol) and Et3N (0.25 mL, 1.77 mmol) in CH3CN (6 mL) was stirred overnight at 80° C. The mixture was poured onto water (˜150 mL), sonicated and filtered to afford the title compound (94 mg, 70%) as a white solid. LC-MS (ES) m/z=227, 229 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]=[C:8]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)C>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1

Procedure:
To a stirred suspension of 10% palladium on carbon (45 mg) in methanol (5 mL) was added a solution of 3-(benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acid tert-butyl ester 29-7b (220 mg) in ethanol (5 mL) and the mixture was subjected to an atmosphere of hydrogen for 48 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 9:1 ethyl acetate/methanol to give 29-8b as a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:6][C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-1-pyridin-3-yl-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (24 mg, 0.062 mmol), β-alanine (552 mg, 6.2 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and concentrated to dryness. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 445.39 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][C:23]=2[C:33]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=2[O:41][CH3:42])=[CH:18][C:17]=1[OH:43].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][C:23]=2[C:33]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=2[O:41][CH3:42])=[CH:18][C:17]=1[O:43][CH2:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7]
Reactant: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(O)c2)n1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Add 0.257 g (2.11 mmol) of 3-chloro-N,N-dimethylpropane-1-amine hydrochloride and 3.40 g (1.34 mmol) of caesium carbonate to a solution of 0.5 g (1.21 mmol) of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 20 mL of anhydrous DMF under argon. Stir the reaction mixture for 15 min at RT then heat for 2 h at 80° C. After cooling to RT, add 1 mL of an aqueous solution of citric acid at 5% and concentrate the whole under reduced pressure. Take up the residue in 50 mL of EtOAc and wash with 10 mL of a 5% solution of Na2CO3 and then 10 mL of water. After drying over Na2SO4 and concentration under reduced pressure, purify the residue by silica gel column chromatography, eluting with a DCM/methanol gradient from 1 to 15% of methanol. After concentration under reduced pressure, we obtain 0.55 g of ethyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of oil.