Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(O[C:9](C)(C)[CH3:10])=O)=NC([O-])=O.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:39])=[CH:28][C:29]=3[O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:40][CH2:41][O:42][C:17]2=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.N>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:39][CH2:9][CH3:10])=[CH:28][C:29]=3[O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:40][CH2:41][O:42][C:17]2=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)[O-]
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of di-(tert-butyl azodicarboxylate (0.26 g) in methylene chloride (1 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.12 g), ethanol (0.019 g), triphenylphosphine (0.15 g) and methylene chloride (2 ml) and the resultant mixture was stirred at ambient temperature for 1 hour. A 2M solution of hydrogen chloride in diethyl ether (3 ml) was added and the mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (1 ml) was added and the precipitate was isolated and dried under vacuum. The solid so obtained was dissolved in a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated. The residue was triturated under pentane and the resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (0.092 g); NMR Spectrum: (CDCl3) 1.5 (t, 3H), 1.95-2.1 (m, 2H), 2.15-2.5 (m, 2H), 2.3 (s, 3H), 2.3-2.4 (m, 2H), 2.7 (br s, 2H), 4.15 (m, 2H), 4.6 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: M+H+ 457 and 459.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[C:21]([F:30])[CH:20]=1)[CH3:17].CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.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].CO.O>[CH2:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH:24]2[CH2:25][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=3)[CH2:27]2)=[C:21]([F:30])[CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(OC2CNC2)c(F)c1
Reactant: C[C@H](NC(=O)N(C)C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)N(C)C)cc3)C2)c(F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere a mixture of 0.080 g (0.295 mmol) (S)-3-[1-(4-bromo-phenyl)-ethyl]-1,1-dimethyl-urea (II.1), 0.073 g (0.295 mmol) 3-(4-ethoxy-2-fluoro-phenoxy)-azetidine (IX.2), 0.117 g (97%, 1.18 mmol) NaOtBu, 0.0035 g (0.118 mmol) 2-(di-tert-butylphosphino)biphenyl, 0.027 g (0.0295 mmol) tris-(dibenzylideneaceton)-dipalladium(0) in 1.5 mL 1,4-dioxane is stirred for 3 h at 80° C. Few water and methanol is added, the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (GeminiC18, methanol/water (+0.3% NH4OH)) to yield the desired product.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:17][C:11]2=[CH:12][N:13]=[C:14]([Br:16])[CH:15]=[C:10]2[CH:9]=1)=[O:7])C>C(O)C>[Br:16][C:14]1[CH:15]=[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[NH:17][C:11]2=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cc2cc(Br)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(Br)ncc2[nH]1

Procedure:
Sodium hydroxide solution (1.1 mL, 2M, 2.23 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 26, 500 mg, 1.86 mmol) in ethanol (20 mL), and the reaction mixture heated under reflux for 1.5 h and then concentrated in vacuo. The residue was dissolved in water (15 mL) and acidified with acetic acid resulting in formation of a brown precipitate. The solid was collected by filtration and dried to give the title compound as a brown solid. δH (d6 DMSO): 7.08 (1H, s), 7.97 (1H, s), 8.60 (1H, s); m/z (ES+)=241 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br.[OH-].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10]
Reactant: COC(CBr)OC
Reactant: N#CC(CCN1CCCCC1)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(CC(C#N)(CCN1CCCCC1)c1ccccc1Cl)OC

Procedure:
The synthesis outlined in Scheme II comprises (a) reacting commercially available 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base, such as sodium hydroxide, and methyltributylammonium chloride to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; (b) alkylating the resulting piperidinebutanenitrile with bromoacetaldehyde dimethyl acetal in dimethylsulfoxide (DMSO) in the presence of potassium hydroxide to produce (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)-1-piperidinebutanenitrile; (c) hydrolyzing the resulting piperidinebutanenitrile in a solvent such as toluene with hydrochloric acid to produce (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)-1-piperidinebutanenitrile; (d) reacting the resulting piperidinebutanenitrile with isopropylamine in a solvent such as toluene in the presence of potassium carbonate to form an imine substituted piperidinebutanenitrile; (e) reducing the resulting imine substituted piperidinebutanenitrile with sodium borohydride and ethanol to form an amino substituted piperidinebutanenitrile; (f) acetylating the resulting amino substituted piperidinebutanenitrile with acetic anhydride in a solvent such as toluene to produce an acetylated amino substituted piperidinebutanenitrile; (g) hydrolyzing the resulting acetylated amino substituted piperidinebutanenitrile with sulfuric acid to produce an acetylated amino substituted-1-piperidinebutanamide; and (h) isolating the resulting 1-piperidinebutanamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:30]=[CH:29][C:16]=2[C:17]([NH:19][C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:25]([O:27]C)=[O:26])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[OH-].[K+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)[CH:30]=[CH:29][C:16]=2[C:17]([NH:19][C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:25]([OH:27])=[O:26])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccsc2C(=O)O)CC1
Yield: 94.4 %

Procedure:
A solution of the methyl 3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-thiophene-2-carboxylate (3.8 g, 7.2 mmol) and EtOH (100 mL) was treated with a solution of KOH (0.88 g) in water (80 mL). The reaction mixture was refluxed overnight, quenched with glacial acetic acid (1.5 mL) and concentrated under vacuum. The resulting aqueous mixture was extracted with EtOAc (2×100 mL). The combined extracts were dried over MgSO4 and concentrated to give 3.5 g (6.8 mmol, 94%) of the acid as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[CH3:15][N:16](C=O)C.O>[C-]#N.[C-]#N.[Zn+2].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:8]([C:5]1[C:4]([C:11]([F:14])([F:13])[F:12])=[CH:3][C:2]([C:15]#[N:16])=[CH:7][N:6]=1)(=[O:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ncc(Br)cc1C(F)(F)F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(=O)c1ncc(C#N)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
Dissolve 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)ethanone (2.67 g, 0.01 mol) in anhydrous DMF/H2O (30.0:0.3 mL) and degas the resulting solution with N2 for 10 minutes. Add Zn(CN)2 (1.17 g, 0.01 mol), Pd2(dba)3 (229 mg, 2.5 mol %) and DPPF (270 mg, 5 mol %). Purge the mixture with N2 for another 10 minutes and heat at 120° C. under N2 atmosphere for 45 minutes. Cool the reaction mixture to room temperature, dilute with water, extract with EtOAc (3×75 mL) and dry (MgSO4). Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to afford the title product as a yellow solid.
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[C:20](Cl)(=[O:22])[CH3:21].C(N(C(C)C)CC)(C)C>ClCCl>[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:20](=[O:22])[CH3:21])[CH2:12][CH2:11]1)=[O:16])(=[O:6])/[CH:4]=[CH:3]/[C:2]([O:18][CH3:19])=[O:17]
Reactant: CC(=O)Cl
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(C(C)=O)CC1
Yield: 59.2 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.20 g, 0.68 mmol) was reacted with acetyl chloride (AcCl) (0.60 mL, 0.66 g, 0.84 mmol) and diisopropylethylamine (0.70 mL, 0.52 g, 4.0 mmol) in dichloromethane (DCM). Following aqueous work-up, the crude product was purified by silica gel flash chromatography to afford 0.12 g (54% yield) of the title compound (16) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.93 (m, 2H), 4.86 (s, 2H), 3.83 (s, 3H), 3.66 3.63 (m, 4H), 3.50-3.40 (m, 4H), 2.14 (s, 3H). MS (ESI): m/z 299.12 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:14][O:15][CH3:16].[Cl-].[NH4+]>CN(C)C=O>[CH3:14][O:15][CH2:16][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cccc(C=O)c1O
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cccc1C=O
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
In N,N-dimethylformamide (50 mL) was dissolved 4.96 g (36.5 mmol) of 2-hydroxy-3-methylbenzaldehyde, 2.19 g (54.6 mmol) of 60% sodium hydride was added to the solution in an ice bath and the resulting mixture was stirred for 10 minutes. To the mixture was added 3.59 mL (47.3 mmol) of chloro(methoxy)methane in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate=50:1) to obtain 6.60 g (36.6 mmol, Yield: 100%) of 2-(methoxymethoxy)-3-methylbenzaldehyde.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CCOCC>[CH3:27][S:28]([O:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1COc2ccc(Oc3ccccc3)cc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)OCC1COc2ccc(Oc3ccccc3)cc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-7-phenoxy-1,4-benzodioxane (1.42 g, 5.50 mmol) and triethylamine (1.11 g, 11.0 mmol) are dissolved in methylene chloride (50 mL) and treated with methanesulfonyl chloride (0.94 g, 8.26 mmol) at 0° C. The mixture is stirred at 0° C. for 30 minutes, and diluted with ether. This is washed with aqueous sodium bicarbonate, aqueous 1N hydrochloric acid and saturated aqueous ammonium chloride, dried over magnesium sulfate and evaporated to give 2-methanesulfonyloxymethyl-7-phenoxy-1,4-benzodioxane. The crude oil is used without further purification.
Reaction SMILES: [NH3:1].CO.C([O:6][C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:17]=2)[N:10]=1)=O)C>CO>[Cl:15][C:13]1[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:17]=2)[N:10]=[C:9]([C:7]([NH2:1])=[O:6])[CH:14]=1
Reactant: N
Reactant: CCOC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Solvent: CO
Product: NC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Reaction time: 3 h

Procedure:
In a 50-ml vial with a screw-top septum, 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid ethyl ester (0.445 g) was dissolved in 3 ml methanol. 7N NH3/MeOH (6 ml) was added to the solution and stirred for 3 hours, at which time the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was suspended in about 3 ml methanol. The suspension was collected by vacuum filtration and washed with cold methanol to provide 0.267 g of 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid amide as a very pure yellow solid (65% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>>[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]=23)=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22]
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(N)=O
Product: CC(C)OC(=O)C(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Yield: 47.3 %

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.060 g, 0.23 mmol) was reacted with isopropyl 3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.057 g, 0.23 mmol) to afford the title compound (0.052 g, 47%) as a light yellow solid. MW=477.98. APCI MS m/z 478 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ncccn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2ncccn2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyrimidin-2-ylethanol (Preparation 61)(59 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was stirred for 72 hours at room temperature. The solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (110 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C1(C)C=C(C)C=C(C)C=1.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: OP(O)O
Solvent: Cc1cc(C)cc(C)c1
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
334 g (2.0 mol) of 4-nitrobenzoic acid, 120 g (2.0 mol) of urea and 2.0 g of phosphorous acid are heated in 1000 ml of mesitylene with stirring at from 158° C. to 163° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and washed with 200 ml of mesitylene. The filter cake is introduced into 1000 ml of water, the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution, and is subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 301.2 g of 4-nitrobenzamide are obtained, having a melting point of from 191° to 194° C. This corresponds to a yield of 90.7% of theory. By acidification of the aqueous mother liquor to pH 2, 12.5 g of 4-nitrobenzoic acid (3.7% of theory) are obtained which can be employed again in a subsequent batch.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1([CH3:27])[C@H:21]2[CH2:22][C@@H:17]1[CH2:18][CH2:19][C@H:20]2[CH2:23][C:24](O)=[O:25]>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C@@H:20]2[CH2:19][CH2:18][C@H:17]3[CH2:22][C@@H:21]2[C:16]3([CH3:15])[CH3:27])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Product: CC(C)(C)c1c(NC(=O)C[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)nn2cccnc12

Procedure:
The product from Example 105B and the product from Example 4B were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.65-9.70 (bs, 1H), 8.92 (dd, J=6.3, 1.8 Hz, 1H), 8.48 (dd, J=4.1, 1.8 Hz, 1H), 6.99 (dd, J=6.7, 3.9 Hz, 1H), 2.52-2.59 (m, 1H), 2.25-2.47 (m, 3H), 1.78-2.00 (m, 5H), 1.48-1.52 (m, 1H), 1.45 (s, 9H), 1.15-1.21 (bs, 3H), 1.02-1.11 (bs, 3H), 0.91 (d, J=9.3 Hz, 1H); MS (DCI) m/z 355 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:23]2[CH:22]=[N:21][CH:20]=[C:19]([F:18])[CH:24]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Reactant: Fc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cncc(F)c2)ccn1
Yield: 65 %

Procedure:
5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.15 g, 0.605 mmol) was dissolved in 5 mL fry DMF. 3,5-Difluoropyridine (0.213 g, 1.85 mmol) and cesium carbonate (0.59 g, 1.85 mmol) were added. The reaction mixture was irradiated in the microwave at 150° C. for 45 min, diluted with 100 mL water and extracted three times with ethyl acetate (50 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0→0:100 gradient to yield the title compound as an off-white solid (0.135 g, 65%), MS (ISP): m/e=344.1 (M+H+).
Reaction SMILES: [Mg].[CH3:2][Si:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(Cl)Cl.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1.C=CC=C>CCOCC.C(O)CO>[CH3:2][Si:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14][CH:13]=[CH:12][CH2:16]1
Reactant: C[Si](Cl)(Cl)c1ccccc1
Reactant: C1CCOC1
Agent: C=CC=C
Agent: [Mg]
Solvent: OCCO
Solvent: CCOCC
Product: C[Si]1(c2ccccc2)CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed active magnesium powder (9.6 g, 0.4 mol), methylphenyldichlorosilane (38.2 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Ethylene glycol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. These were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. The expected compound, bp 105°-107° C., 5 mm Hg, 42% yield, was collected.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[C:7]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:8]=1>CCOC(C)=O.O=[Pt]=O>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:16])[F:17])=[C:7]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:8]=1
Reactant: Fc1ccc(C(F)(F)F)c(C2=CCNCC2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
A mixture of 4-(5-fluoro-2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10, 0.393 g, 1.41 mmol) and PtO2 (0.095 mg, 0.42 mmol) in EtOAc (14 mL) was stirred at ambient temperature for 18 h under a balloon of H2. The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (4 mL). To this solution was added HCl (2 N in Et2O, 4.0 mL) and the resulting mixture stirred at ambient temperature for 20 min. The resulting suspension was diluted with Et2O (20 mL) and the solids were collected by filtration to provide 4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (11) as a white solid (309 mg, 78%): 1H NMR (300 MHz, DMSO-d6) δ 8.81 (br s, 2H), 7.80 (dd, J=9.3, 6.0 Hz, 1H), 7.39-7.26 (m, 2H), 3.43-3.30 (m, 1H, overlaps with H2O), 3.24-2.97 (m, 3H), 2.11-1.90 (m, 2H), 1.88-1.75 (m, 2H); ESI MS m/z 248 [M+H]+.