Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:12]1[CH:11]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C2CC2)nc(-c2cccc(Cl)c2)[nH]1
Product: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
A 250-mL round bottom flask was charged with 2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4(3H)-one (2.46 g, 9.97 mmol). POCl3 (11.0 mL, 120 mmol) was cautiously added at 0° C. The resulting mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) treated with aqueous sodium bicarbonate until the pH˜8. The aqueous layer was extracted with dichloromethane (4×25 mL). The combined organic extract was washed the saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography using hexanes/dichloromethane (3:1) as eluent to afford the title compound (2.55 g, 96%) as a white solid. MW=265.14. 1H NMR (CDCl3, 500 MHz) δ 8.38 (t, J=1.5 Hz, 1H), 8.28 (dt, J=8.0, 1.5 Hz, 1H), 7.44 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12 (s, 1H), 2.04-1.97 (m, 1H), 1.33-1.27 (m, 2H), 1.18-1.13 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=23)O1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:4]1[N:3]=[C:2]([C:44]2[CH:45]=[N:46][N:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=23)[CH:7]=[N:6][CH:5]=1
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Reactant: Clc1cncc(Cl)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Clc1cncc(-c2cnn3ccccc23)n1
Yield: 33.1 %

Procedure:
2,6-Dichloropyrazine (0.316 g, 2.12 mmol), tris(dibenzylideneacetone)dipalladium (0), (0.097 g, 0.106 mmol), tricyclohexylphosphine (0.06 g, 0.212 mmol) and potassium phosphate (1.35 g, 6.36 mmol) were added to a suspension of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (Preparation 27a, 0.518 g, 2.12 mmol)) in N,N′-dimethylformamide (10 mL). This mixture was subjected to microwave irradiation at 100° C. for 40 min. The reaction mixture was filtered through Celite®, eluting with methanol, and the filtrate was evaporated. The resulting residue was purified by flash chromatography (2:8 to 3:7 ethyl acetate/hexane) to yield the title compound (0.162 g, 33%, two steps) as a pale yellow solid.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)[CH2:39][CH2:38]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Cl)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 85 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:9]1[CH:17]=[CH:18][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
2-(4-Ethoxycarbonylphenoxy)pyridine (2.43 g, 9.99 mmol), 90 mL of ethanol and 50 mL of 1 mol/L aqueous solution of sodium hydroxide were mixed and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated and the residue was brought to pH3 to 4 with dilute hydrochloric acid. The precipitates produced were filtered, washed with water, and then dried to obtain 2.07 g (96%) of the title compound as colorless powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH2:30][CH3:31]>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([O:19][CH2:30][CH3:31])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1c(C#N)ncc2c1c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (120 mg, 0.28 mmol) in anhydrous THF (5 mL) was cooled to 0° C. and treated with sodium hydride (60% dispersion in mineral oil; 12 mg, 0.30 mmol). After gas evolution had ceased, iodoethane (424 μL, 4.10 mmol) was added and the mixture stirred at ambient temperature overnight then heated at 60° C. for 5 h. The reaction was then allowed to cool, diluted with toluene and concentrated in vacuo. The residue was purified by column chromatography (silica, 2 g column, Si II SPE, 10-100% ethyl acetate in DCM) to afford the title compound as a yellow solid (30 mg, 23%). 1H NMR (DMSO-D6, 400 MHz): 8.86 (s, 1H), 8.77 (s, 2H), 8.24-8.22 (m, 1H), 8.22-8.20 (m, 1H), 7.81-7.75 (m, 1H), 7.68-7.61 (m, 2H), 4.75 (q, J=7.2 Hz, 2H), 1.64 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=3.30 min, M+H+=457/459.
Reaction SMILES: [CH3:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:3]([OH:5])=[O:4]
Reactant: CC(C)=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 95.9 %

Procedure:
A solution of Example 28A (2.51 g, 8.14 mmol) in ethyl acetate (20 mL) was treated with 10% palladium on carbon (0.251 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (1.72 g, 96%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (m, 6 H) 1.09 (m, 2 H) 1.51 (m, 4H) 1.98 (m, 2 H) 7.34 (m, 5 H). MS (DCI NH3+) m/z 238 (M+NH4)+.
Reaction SMILES: [CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:21]=[C:22]([CH2:28][C:29]([OH:31])=[O:30])[CH:23]=[N:24][C:25]=2[O:26]C)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:36][CH2:37]O>C(Cl)Cl.O>[CH2:36]([O:31][C:29](=[O:30])[CH2:28][C:22]1[CH:23]=[N:24][C:25]([OH:26])=[C:20]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:19])[F:17])=[CH:15][C:10]=2[CH2:9][N:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:7][CH3:8])[CH:21]=1)[CH3:37]
Reactant: CCO
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)cnc1OC)C(=O)C1CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)Cc1cnc(O)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (5-{2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid (0.099 g, 0.22 mmol) in EtOH (1 mL) was added thionyl chloride (0.16 mL, 2.19 mmol), and the reaction was stirred at 80° C. overnight. The mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give (5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-hydroxy-pyridin-3-yl)-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=S)=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.[CH:39]1([C:42]([NH:44][NH2:45])=O)[CH2:41][CH2:40]1.C(Cl)Cl>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[CH:39]1([C:42]2[N:28]3[CH2:29][CH2:30][CH2:31][C@@H:26]([C:13]4[N:9]5[CH:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]6[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=6[O:2][CH3:1])[C:8]5=[C:15]([C:16]5[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=5)[N:14]=4)[C:27]3=[N:45][N:44]=2)[CH2:41][CH2:40]1
Reactant: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=S)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Reactant: NNC(=O)C1CC1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc([C@@H]3CCCn4c(C5CC5)nnc43)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a solution of (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-thioxopiperidin-3-yl) imidazo[1,5-a]pyrazin-1-yl)benzoate (600 mg, 1.13 mmol) in THF (20 mL) was added cyclopropanecarbohydrazide (339 mg, 3.39 mmol) and Hg(OAc)2 (360 mg, 1.13 mmol). The mixture was stirred at RT for 20 minutes and then heated to 65° C. overnight. The reaction mixture was filtered and the filtrate was evaporated, the residue was purified by column chromatography on silica gel eluted with EA:DCM:THF=1:1:1 to give (S)-methyl 4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (300 mg, yield 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:15]([F:16])=[C:14]([CH2:17]Br)[CH:13]=[CH:12][C:11]=2[Cl:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:20]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:15]([F:16])=[C:14]([CH2:17][NH2:20])[CH:13]=[CH:12][C:11]=2[Cl:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 2-[(3-bromo-5-chlorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (2.0 g, 4.7 mmol) in CH2Cl2 (10 mL) was added ammonia in methanol (7N, 100 mL). The reaction mixture was stirred for 4 h and concentrated. The resulting crude material was triturated from water to afford the title compound (1.55 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d5): δ ppm 7.57-7.49 (m, 3H), 7.12-7.11 (m, 1H), 7.05-7.04 (m, 1H), 5.99 (br s, 2H), 3.95 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[CH:28]=[C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:26]=[CH:25][C:22]=3[C:23]#[N:24])=[C:3]([CH3:19])[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (150 mg, 0.55 mmol), 2-amino-4-morpholinobenzonitrile (112 mg, 0.55 mmol) and a 4.0M solution of HCl in dioxane (0.028 mL, 0.11 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-((7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinyl)amino)-4-(4-morpholinyl)benzonitrile was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 8.87 (1H, dd, J=2.0, 0.5 Hz), 8.73 (1H, dd, J=4.9, 1.7 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.92 (1H, dd, J=9.3, 5.9 Hz), 7.80 (1H, dd, J=9.8, 2.4 Hz), 7.44-7.51 (2H, m), 7.33 (1H, ddd, J=9.2, 8.0, 2.6 Hz), 6.46 (1H, s), 6.43 (1H, dd, J=8.9, 2.3 Hz), 5.72 (1H, d, J=2.2 Hz), 3.63-3.76 (4H, m), 2.95-3.09 (4H, m), 2.35 (3H, s). Mass Spectrum (ESI) m/e=440.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](C)=[CH:13][CH:12]=1)[CH3:10]>B([O-])([O-])[O-].[Al+3].[Cu+2]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:10]=[CH:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCc1ccc(C)cc1
Agent: [Cu+2]
Agent: [Al+3]
Agent: [O-]B([O-])[O-]
Solvent: CCc1ccccc1
Product: C=Cc1ccccc1

Procedure:
The doped copper aluminum borate catalyst prepared in the preceding paragraph was ground to 18 to 40 mesh and used in the dehydrogenation of ethylbenzene and p-ethyltoluene in the manner described in Example I. The ethylbenzene runs were carried out at a 0.9 liquid hour space velocity, 620° C. temperature, steam:ethylbenzene molar ratio of 20:1, yielding 42% conversion and 72% selectivity to styrene. The p-ethyltoluene conversion to p-methylstyrene was carried out using a 0.2 liquid hour space velocity, 620° C. temperature, 15:1 molar ratio of steam to p-ethyltoluene, a 5:1 toluene to p-ethyltoluene dilution, yielding 68% conversion and 93% selectivity to p-methylstyrene.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16](Cl)=[O:17])[CH:12]=1>>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[NH2:1])=[O:17])[CH:12]=1
Reactant: NCc1ccccc1N
Reactant: Cc1cc(C(=O)Cl)no1
Product: Cc1cc(C(=O)NCc2ccccc2N)no1

Procedure:
2-Aminobenzylamine (490 mg, 4.01 mmol) and 5-methyl-3-isoxazoyl chloride (437 mg, 3.01 mmol) were converted to the title compound by the procedure of Preparation 1 to yield 250 mg. (36%). MS(FD) m/z 231 (M+). 1H NMR consistent with desired product.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[I:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[NH2:20].N1C=CC=CC=1>ClCCl>[I:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([F:18])([F:19])[F:17])=[CH:11][C:10]=1[NH:20][C:2](=[O:3])[O:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cc(I)c(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(I)c(NC(=O)OC(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
Add a solution of isopropyl chloroformate (99.6 mL, 99.6 mmol, 1M in toluene) dropwise to a solution of 2-iodo-4-methyl-5-trifluoromethylphenylamine (27.26 g, 90.55 mmol) and pyridine (14.6 mL, 181.1 mmol) in dichloromethane (350 mL) at 5° C. under an atmosphere of nitrogen and warm the mixture to room temperature. Stir for 3 h and wash the mixture with 2 N HCl (100 mL) and brine (100 mL). Dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a tan solid (33.59 g, 96%), which is used in the next step without purification. APCI MS m/z 388 (M+H)+.
Reaction SMILES: [CH:1]([Si:3]([CH3:6])([CH3:5])[Cl:4])=[CH2:2].[CH2:7]([SiH:10]([Cl:12])[Cl:11])[CH:8]=[CH2:9]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:5][Si:3]([Cl:4])([CH3:6])[CH2:1][CH2:2][Si:10]([Cl:12])([Cl:11])[CH2:7][CH:8]=[CH2:9]
Reactant: C=CC[SiH](Cl)Cl
Reactant: C=C[Si](C)(C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CC[Si](C)(C)Cl
Yield: 88.4 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 25.3 g (0.21 mol) of vinyldimethylchlorosilane and 50 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 10 g (0.07 mol) of allyldichlorosilane for 30 rain at 80° C. and the solution was further reacted for 2 hrs to complete the reaction. Vacuum distillation (48°-52° C./0.5 torr) of the product mixture gave 16.2 g (89%) of 7-methyl-4,4,7-trichloro-4,7-disila-1-octene.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[CH:28]=1)([O-:17])=[O:16].C(O)(=O)C.C=O>C(#N)C.O.CCOC(C)=O>[CH3:1][N:23]1[C:22]2[CH:28]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=[CH:20][C:21]=2[O:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCCOc2ccc([N+](=O)[O-])cc21
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
Sodium triacetoxyborohydride (1.02 g, 4.82 mmol) was added to 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.312 g, 1.61 mmol) in Acetonitrile (15 mL) and Acetic acid (0.20 mL, 3.5 mmol), then 13 M of Formaldehyde in Water (0.60 mL) was added. After 45 min, the mixture was poured into 100 mL EtOAc and washed with satd. sodium bicarbonate (3×30 mL) and brine (50 mL). After drying over sodium sulfate and conc. the residue was chromatographed (ISCO, 40 g, 0-40% EtOAc:Hex) to afford 9-Methyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (298 mg, 89%). 1H-NMR (CDCl3): 7.65 (d, 1H, J=8.6 Hz), 7.61 (s, 1H), 6.91 (d, 1H, J=8.6 Hz), 4.29 (t, 2H, J=5.8 Hz), 3.33 (t, 2H, J=6.0 Hz), 2.86 (t, 3H), 2.08 (tt, 2H, J=5.8, 6.0 Hz)
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].C1N2CCN(CC2)C1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][O:5][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: CCC(CC)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CCC(CC)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 2-ethyl-1-butanol (1.00 g, 9.79 mmol), triethylenediamine (1.32 g, 11.7 mmol) in DCM (30 mL, 0.5 mol) cooled to 0° C. was added p-toluenesulfonyl chloride (1.96 g, 10.3 mmol) in DCM (10 mL) The reaction mixture was stirred for 30 min, and extracted with 1.0N NaOH (2×40 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and isolated by rotary evaporation to give the title compound (2.40 g).
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].[H-].[Na+].C(C1C=C(C=CC=1)[O-])=O.[Na+].[Na]>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:22]([C:21]1[CH:20]=[C:19]([OH:18])[CH:26]=[CH:25][CH:24]=1)[OH:23]
Reactant: O=Cc1cccc(O)c1
Reactant: Clc1cccc(OCCCCCBr)c1
Agent: II
Agent: O=Cc1cccc([O-])c1
Agent: [H-]
Solvent: C1CCOC1
Product: Oc1cccc(C(O)CCCCCOc2cccc(Cl)c2)c1
Reaction time: 0.1 h
Yield: 78 %

Procedure:
To a gently refluxing dry tetrahydrofuran (75 ml) containing magnesium turnings (1.3 g; 53 mmol) and a small crystal of iodine, was added dropwise from a dropping funnel a solution of 5-(3-chlorophenoxy)pentyl bromide (13.87 g, 50 mmol) in dry THF (55 ml). After about 5-7 minutes, the Grignard reaction started as indicated by the disappearance of the brown iodine color. The heating was adjusted so that the solution refluxed gently. After the addition of the halide was complete (ca. 30 min.), the clear solution was refluxed for about 1 hour. This solution of the Grignard reagent was cooled to room temperature. A solution of 3-hydroxybenzaldehyde (5.5 g, 45 mmol) in dry THF (50 ml) was added dropwise to a well-stirred suspension of sodium hydride (2.8 g, 58 mmol) (50% oil dispersion) in dry THF (75 ml) at room temperature. The temperature was not allowed to go above ca. 40° C. After the addition of 3-hydroxybenzaldehyde was complete (ca. 30 min.) the slightly cloudy solution was warmed to 45°-50° C., and the stirred for 1 hour at this temperature. The resulting clear solution of sodium 3-formyl phenoxide was cooled to room temperature, and added dropwise, using a cannula, to the well-stirred solution of the Grignard reagent (whose preparation was described above). A thick precipitate immediately formed, and the solution was difficult to stir. This reaction mixture was maintained 40°-45° C. during the addition of the sodium salt. After the addition was complete (ca. 2 hours), the reaction mixture was stirred at this temperature for another hour, and then cooled in an ice bath. The excess reactive materials (sodium hydride, Grignard reagent, etc.) were destroyed slowly by carefully adding methanol (30 ml), and then a saturated ammonium chloride solution (350 ml) was added to dissolve all solids. The organic layer was separated, and the aqueous layer was extracted with ether (2×75 ml). The combined organics were washed with water, brine, and then dried over anhydrous magnesium sulfate. After drying the extract, all volatiles were removed to obtain a dark liquid. This oil was triturated with a 1:1 mixture of ether and petroleum ether (35°-55° C.) until an off-white solid was obtained (11.1 g; 78% yield). This can be crystallized from methanolethyl acetate to give a white solid, m.p. 125°-127° C.; mass spectrum: m/e (intensity observed at 320 (86.9%) and 322 (29.5%) which correspond to the molecular ion. The crude material was, however, pure enough to be used for the next reaction.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])[CH:24]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cccnc2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
A solution of nicotinic acid (42 mg, 0.34 mmol) and 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyridine-3-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (21 mg, 15%) as a white solid: LC/MS m/e calcd for C24H23N3O3 (M+H)+: 402.47, observed: 402.1.