Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)=[O:29]
Reactant: Fc1ccc(-c2nc(N3CCNCC3)nc3c2CCC3)cc1
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccco1)N1CCN(c2nc3c(c(-c4ccc(F)cc4)n2)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-cyclopentapyrimidine (1.0 g), 2-furoic acid (0.38 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.79 g) and chloroform (40 ml) is stirred at room temperature for 2 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene, and the solution is subjected to silica gel column chromatography. The fractions eluted with toluene-ethyl acetate (9:1) are collected, and the product therefrom is recrystallized from ethanol to give the desired compound (0.62 g), m.p. 124°-125° C. (ethanol).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1>CN(C=O)C>[BrH:1].[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][S:22][C:20]2[NH:21][C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:24]=[CH:23][C:18]=3[N:19]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc2nc(S)[nH]c2c1
Solvent: CN(C)C=O
Product: Br
Product: COC(=O)c1ccc(CSc2nc3ccc(OC)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.1 %

Procedure:
To a solution of methyl 4-(bromomethyl)benzoate (2.51 g, 11.0 mmol) in DMF (50 mL) was added 5-methoxy-2-benzimidazolethiol (1.98 g, 11.0 mmol). The mixture was stirred at room temperature for 24 h and the solvent was evaporated in vacuo. The residue was suspended in ethyl acetate and the hydrobromide salt was collected by filtration to afford the title compound 234 (4.10 g, 91% yield) as a colorless solid. 1H NMR: (DMSO-d6) δ (ppm): 7.90 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (s,1H), 6.94 (d, J=8.2 Hz,1H), 4.65 (s,2H), 3.82 (s,3H), 3.79 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
1 g of 2-Fluoro-5-Nitro benzotrifluoride (4.78 m.moles) was dissolved in 3 ml of DMF. To this solution was added 640 mg (5 m.moles) of 2-chloro-phenol and 2.76 grams of potassium carbonate. The reaction mixture was heated for 4 hours at 100° C. The reaction was cooled to room temperature and 200 ml of water added. It was then extracted 4 times with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent evaporated to yield a pale yellow oil. It was purified using silica-gel column chromatography (1:3 ethyl acetate hexane) to yield 1.15 g (87.5% yield) of pure 1-Chloro-2-[4-Nitro-2-(Trifluoromethyl)phenoxy]benzene as product.
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH:21]=[CH:22][C:23]3[CH:24]=[C:25]([C@@H:29](OS(C)(=O)=O)[CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([OH:41])([CH3:40])[CH3:39])[CH:26]=[CH:27][CH:28]=3)=[N:18]2)=[CH:13][CH:12]=1>>[CH3:40][C:38]([OH:41])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH2:30][C@@H:29]([S:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1)[C:25]1[CH:26]=[CH:27][CH:28]=[C:23](/[CH:22]=[CH:21]/[C:17]2[CH:16]=[CH:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:20][C:19]=3[N:18]=2)[CH:24]=1)[CH3:39]
Reactant: O=C(O)CC1(CS)CC1
Reactant: CC(C)(O)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
In U.S. Pat. No. 5,614,632, montelukast is prepared by condensing 1-(mercaptomethyl)cyclopropaneacetic acid then condensation with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol compound to afford Montelukast. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1)[CH:11]=[CH2:12].[OH-:39].[Na+].OO>O1CCCC1.C(O)C>[OH:39][CH2:12][CH2:11][CH2:10][O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1
Reactant: C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](OCCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reaction time: 6 h

Procedure:
To a solution of 0.17 g of 9-borabicyclo[3.3.1]nonane in 35 ml of dry tetrahydrofuran, 0.50 g of 3β-(prop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 10 ml of tetrahydrofuran were added under nitrogen atmosphere, at room temperature. The solution was stirred for 6 hrs then 0.75 ml of ethanol, 0.25 ml of sodium hydroxide 6N and 0.50 ml of hydrogen peroxide 30% were added. The mixture was stirred at 50° C. for an hr, quenched with a solution of 0.76 g of potassium carbonate in 20 ml of water and the organic solvent distilled under reduced pressure. The residue was extracted with methylene chloride, the organic solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 70/30 as eluant to give 0.40 g of 3β-(3-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white amorphous solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[C:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:20])[CH3:19]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)n1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 1H-indole-3-carboxaldehyde (300 mg, 2.07 mmol) in 6.2 mL of dry dichloromethane were added pyridine (0.34 mL, 4.2 mmol), acetic anhydride (0.59 mL, 6.2 mmol), and N,N-dimethylaminopyridine (20 mg, 0.16 mmol) at room temperature, successively. After being stirred at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was rinsed with diethyl ether/hexane to obtain the title compound as a white powder (235 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH: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:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].C([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(C)(C)C>>[CH2:35]([O:34][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:52]4[CH2:51][CH2:50][N:49]([CH2:48][C:47]([OH:46])=[O:55])[CH2:54][CH2:53]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:31][CH2:32][CH3:33])=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 251 using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 722.28 (100) [MH+]; HPLC: tR=0.80 min (UPLC, purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[C:36](O)=[O:37])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:19][C:36]([C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][N:30]1[S:27]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=1)(=[O:29])=[O:28])=[O:37])[CH:13]=2
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)[C@@H]3CCCCN3S(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (35 mg, 0.13 mmol) in CH2Cl2 (5 mL) was added (S)-1-(4-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid (37 mg, 0.13 mmol) and HATU (49 mg, 0.13 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded (S)-1-(4-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid[2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-amide (60 mg, 86%) as a white solid. MH+ 543.0.
Reaction SMILES: [BH:1]([O:3][BH:4][OH:5])[OH:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH:6]12[CH2:12][CH:6]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:7]3)[CH2:7]1)[CH2:11]2.[BH:1]1[O:3][BH:4][O:5][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:9]([CH3:10])([CH3:8])[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:2]1
Reactant: OBOBO
Reactant: Cc1ccccc1
Product: C1C2CC3CC1CC(C2)C3
Product: CC1(C)C(c2ccccc2)OBOBOC1c1ccccc1

Procedure:
The above crude diboronic acid and 2,2-dimcthylporpane-1,3-diol (neopentyl glycol) (10.4 g, 0.1 mol) were dissolved in 300 mL of toluene and heated under vigorous reflux with a Dean-Stark trap overnight. After the completion of the reaction, toluene was evaporated and the crude product was recrystallized from toluene to give 7.10 g of product as white solid. 1H NMR (CDCl3) δ (ppm): 1.00 (s, 12H, CH3), 1.78 (s, 2H), 1.96 (s, 8H), 2.05 (s,2H) 2.30 (s, 2H), 3.74 (s, 4H, CH2), 7.37 (d, J=8.1 Hz, 4H, aromatic), 7.75 (d, J=8.1 Hz, 4H, aromatic); 13C NMR (CDCl3): 21.91, 29.60, 31.87, 35.97, 37.46, 42.23, 48.59, 72.28, 124.17, 128.16, 133.87, 153.21. M.p. 249-251° C.; FD-MS: m/z 512 (M+).
Reaction SMILES: [Li].C(NC(C)C)(C)C.C=CC1C=CC=CC=1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>O1CCCC1>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:23][C:21]2[O:20][N:19]=[C:18]([CH3:17])[CH:22]=2)=[CH:33][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(OCCCCCCBr)cc1
Reactant: Cc1cc(C)on1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C=Cc1ccccc1
Product: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a suspension of 301 mg of lithium wire (1/4 inch portions) in 10 ml of tetrahydrofuran under nitrogen was added 6.72 ml of diisopropylamine and 3.44 ml of styrene while maintaining the temperature at 25° C. The mixture was stirred until all the lithium had dissolved (about four hours) and then cooled to -55° C. 3,5-Dimethylisoxazole (4.3 g) in 10 ml of tetrahydrofuran was then added dropwise and the mixture stirred for an hour at -55° C. 4-(6-Bromohexyloxy)benzonitrile (12 g) in 10 ml of tetrahydrofuran was then added dropwise over a period of one hour, and the mixture was allowed to warm to room temperature and stirred for three days. The solvent was removed in vacuo, the residue treated with 5% ammonium chloride solution and extracted with ether. The ether extracts were dried and concentrated, and the residue subjected to high pressure liquid chromatography with ether-hexane (1:1) mixture to give 3.9 g of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole, used directly in the next reaction.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[NH:23][CH2:22][C:21]3[CH:27]=[N:28][N:29]([CH3:30])[C:20]=3[C:19]=2[CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[N:23]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:22][C:21]3[CH:27]=[N:28][N:29]([CH3:30])[C:20]=3[C:19]=2[CH:18]=1
Reactant: Cn1ncc2c1-c1cc(Cl)ccc1NC2
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cn1ncc2c1-c1cc(Cl)ccc1N(C(=O)C1CC1)C2
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (1.5 ml) was addded dropwise to a mixture of N,N-dimethylaniline (2.4 ml), 4-dimethylaminopyridine (5.0 mg) and 8-chloro-4,5-dihydro-1-methyl-1H -pyrazolo[4,3-c]quinoline (2.0 g) in chloroform (20 ml) at 0° C. and the mixture was allowed to stir at that temperature for 2 hours. After the solvent was evaporated in vacuo, the residue was mixed with 5% hydrochloric acid and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and water and then dried over magnesium sulfate. The solvent was evaported in vacuo to give light brown powder (2. 0 g), which was recrystallized from a mixture of n-hexane and ethyl acetate to afford 8-chloro-5-cyclopropylcarbonyl-4,5-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinoline as colourless prisms.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=2)O1>>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:32][CH:33]=1.[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:21])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)nc3)c(F)cn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)nc3)c(F)cn2c1=O

Procedure:
Ethyl 8-(6-aminopyridin-3-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (93.7 mg, 0.43 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2OC(=O)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:15][C:16]([F:25])([CH3:24])[C:17]#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].ClC1C=CC=C(Cl)C=1>>[F:15][C:16]([C:17]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])([F:25])[CH3:24]
Reactant: CCOC(=O)C#CC(C)(F)F
Reactant: CCc1ccc(-c2nsc(=O)o2)cc1
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(C)(F)F
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Into a 10-mL sealed tube, was placed 5-(4-ethylphenyl)-2H-1,3,4-oxathiazol-2-one (227 mg, 1.10 mmol, 1.00 equiv), ethyl 4,4-difluoropent-2-ynoate (357 mg, 2.20 mmol, 2.01 equiv), 1,3-dichlorobenzene (3 mL). The resulting solution was stirred for 16 h at 150° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 0.191 g (54%) of ethyl 5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazole-4-carboxylate as orange oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[Cu](C#N)[C:21]#[N:22]>CN(C=O)C>[C:21]([C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)#[N:22]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(C#N)nc1-2
Yield: 74.3 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (740, 2.3 mmol) and copper cyanide (537 mg, 6.9 mmol) were mixed in DMF (8 mL). The reaction was microwaved on 200 watts, 150° C. for 40 minutes. The reaction mixture was partitioned between 15% ammonia in water and EtOAc. The aqueous layer was extracted with EtOAc three times, combined organic extracts were washed with water, brine and dried over MgSO4 to produce 0.46 g (74% yield) of methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide (Example 29b) and ethyl 3-oxobutanoate as a bright yellow solid (62%). 1H NMR (400 MHz, DMSO-d6) δ 1.26 (s, 6H), 1.34 (t, J=8.0 Hz, 3H), 1.40-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.74-1.77 (m, 2H), 2.57 (s, 3H), 4.09 (q, J=4.0 Hz, 1H), 4.15 (s, 2H), 4.33 (q, J=8.0 Hz, 2H), 6.89 (d, J=4.0 Hz, 1H), 7.26 (dd, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 8.09 (brs, 2H). MS 414 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.CCN(C(C)C)C(C)C.Cl[CH2:31][O:32][CH3:33].O>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH2:31][O:32][CH3:33])([CH3:18])[CH2:13]1
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]methanol (0.20 g, 0.72 mmol) in dry DCM (10 ml) at 0° C. was added DIPEA (0.42 ml) and chloromethylmethyl ether (0.11 ml). The reaction mixture was stirred at RT for 16 h. Water was added and the product was extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([O:29]C)=[O:28].O[Li].O>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12
Agent: [Li]O
Solvent: O
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Yield: 85.1 %

Procedure:
This material was prepared by the reaction of methyl 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylate 117a (200 mg, 0.46 mmole) with LiOH.H2O (192 mg, 4.6 mmole) in a manner as previously described for example 11c to give a yellow solid (165 mg, 85%). 1H NMR (DMSO-d6, 300 MHz): δ8.57 (1H, d, J=5.46 Hz), 8.45 (1H, d, J=8.85 Hz), 8.00 (2H, s), 7.53 (1H, s), 7.40 (1H, dd, J=2.35, 8.95 Hz), 7.22 (1H, s), 6.79 (1H, d, J=5.46 Hz), 4.00 (3H, s), 2.82 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: COc1cccc(Cl)c1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(Cl)c1F
Temperature: -70 °C

Procedure:
1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 20 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After one hour at −70° 3.93 ml DMF in 7 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 15 ml of a 1M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel to yield 0.25 g 2-chloro-3-fluoro-4-methoxybenzaldehyde. 1H-NMR (CDCl3); δ=3.98 (s, 3H), 6.98 (dd, 1H), 7.75 (dd, 1H), 10.30 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH:9]1([CH2:15][C:16]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([N:37]=[C:38]=[O:39])[CH:31]=1.N12CCCN=C1CCCCC2>ClCCl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([NH:37][C:38]([N:26]2[CH2:25][CH2:24][CH:23]([C:20]3[S:21][CH:22]=[C:18]([C:16](=[O:17])[CH2:15][CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]4)[N:19]=3)[CH2:28][CH2:27]2)=[O:39])[CH:31]=1
Reactant: Cc1ccc(Cl)cc1N=C=O
Reactant: O=C(CC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NC(=O)N1CCC(c2nc(C(=O)CC3CCCCC3)cs2)CC1
Reaction time: 0.08 h
Yield: 91.5 %

Procedure:
Triethylamine (0.047 ml) was added to a mixture of 4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidinium chloride (100 mg) in dichloromethane (1 ml). After the solid had dissolved completely, 4-chloro-2-isocyanato-1-methylbenzene (51 mg) and a drop of 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The reaction mixture was then stirred for 5 minutes. Solvent and triethylamine were removed under reduced pressure. Purification of the residue by column chromatography gave N-(5-chloro-2-methylphenyl)-4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide (128 mg).