Azzindani/Open_Reaction_Data huggingface dataset:
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]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:32]=[CH:31][CH:30]=[C:29]([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])[CH:28]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(N1CCc2ccc(Cl)c(-c3cccc(-c4ccccc4)c3)c2CC1)C(F)(F)F

Procedure:
Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol), 3-biphenylboronic acid (280 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol) and cesium fluoride (144 mg, 0.94 mmol) in anhydrous DME (8 mL) and reflux the mixture for 3 h. Cool the reaction mixture and partition between brine and EtOAc. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 7:3 gradient) to obtain 6-(biphenyl-3-yl)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH2:30])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1.C(N(C(C)C)C(C)C)C.CN(C1C=CC=CN=1)C.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][C:59]=1[O:60][CH3:61])[C:54](Cl)=[O:55]>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH:30][C:54](=[O:55])[C:53]2[CH:57]=[CH:58][C:59]([O:60][CH3:61])=[C:51]([O:50][CH3:49])[CH:52]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1
Reactant: Cc1cc(C)nc(OC(C(=O)O)C(OCCN)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1ccc(C(=O)NCCOC(c2ccccc2)(c2ccccc2)C(Oc2nc(C)cc(C)n2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 1.0 g (2.5 mmol) of 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-aminoethoxy)-3,3-diphenylpropionic acid in 10 ml of methylene chloride was successively admixed at room temperature with 0.35 g (2.7 mmol) of N-ethyldiisopropylamine, 0.03 g (0.2 mmol) of dimethylaminopyridine and 0.54 g (2.7 mmol) of 3,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature for 4 days and then diluted with diethyl ether and extracted with 1M hydrochloric acid and 1M aqueous sodium hydroxide solution, and the combined alkaline phases were made acidic and extracted with ether. The organic phase was dried over sodium sulfate, the solvent was distilled off and the residue (0.9 g) was chromatographed over silica gel (methylene chloride/methanol 9:1). Yield: 280 mg of a white foam.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1>CN(C)C=O.O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reaction time: 3.5 h
Yield: 98.8 %

Procedure:
Add a solution of tert-butyldimethylsilyl chloride (5.0 g, 33.1 mmol) in dimethylforamide (DMF) (70 mL) dropwise over 15 minutes to a solution of 6-bromohexanol (5.0 g, 27.6 mmol) and imidazole (4.7 g, 69 mmol) in DMF (80 mL) at 0° C. under nitrogen protection and stir the mixture for another 3.5 hours. Dilute the mixture with water (400 mL) and extract with diethyl ether (3×150 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the crude product by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:19), to provide (6-bromohexyloxy)-tert-butyldimethylsilane (8.05 g, 98%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.Cl.[CH3:15][NH:16][OH:17].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N+:16]([O-:17])[CH3:15])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CNO
Reactant: O=C(Cn1ccnc1)c1ccco1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: C[N+]([O-])=C(Cn1ccnc1)c1ccco1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.4 %

Procedure:
Under a nitrogen atmosphere, a mixture of 21.32 g (0.121 mol) of 1-(2-furanyl)-2-(1H-imidazol-1-yl)ethanone (3), 15.16 g (0.182 mol) of N-methylhydroxylamine hydrochloride, and 14.89 g (0.182 mol) of sodium acetate in 400 ml of ethanol is stirred at ambient temperature for 4 days. Sodium bicarbonate (30.58 g, 0.364 mol) is added and the mixture filtered. The filtrate is concentrated in vacuo and flash-chromatographed on neutral silica gel using a 98:2 by volume mixture of chloroform and methanol as eluent to give 8.30 g (33%) of compound 4, melting point 130°-133° C. (ethyl acetate). Anal. Calcd. for C10H11N3O2 : C, 58.53; H, 5.40; N, 20.48. Found: C, 58.60; H, 5.47; N, 20.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]#[C:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:20][NH2:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)C#CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)n[nH]1

Procedure:
To a solution of the intermediate from step B (4.74 g, 15.84 mmol) in DMF (30 mL) was added hydrazine (1.58 mL, 35% by wt., 17.43 mmol). After stirring the reaction at room temperature for 18 hours, it was concentrated in vacuo. The residue was suspended in ethyl acetate and washed with water (2×) and saturated NaCl solution (2×). The organic layer was dried over anhydrous MgSO4 filtered and concentrated in vacuo. 1H NMR (CDCl3, 500 MHz): 8.02 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.07 (s, 1H), 1.66 (s, 9H). LC-MS=2.52 min; (M+H−56)=257.1.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][S:7](Cl)(=[O:9])=[O:8]>C1COCC1>[C:1]([NH:5][S:7]([CH3:6])(=[O:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C

Procedure:
t-Butylamine (105 ml, 1.0 mole) was dissolved in THF (about 950 ml) and cooled to 0° C. Methanesulfonylchloride (57.2 g) was added and the solution allowed to warm to room temperature overnight. The mixture was filtered and the filtrate stripped to dryness. The resulting residue was dissolved in methylene chloride and washed with 1N HCl followed by washing first with water and then with brine (water saturated with NaCl). The methylene chloride layer was dried over Na2SO4, filtered, and stripped to dryness. The resulting residue was dissolved in pentane, and the solid which crystallized was collected and dried.
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl N-[(pent-4-enyloxy)carbonyl]-norleucinate (8.50 g, 33.03 mmol) in THF (20 mL) was added 1 N NaOH (20 mL). This reaction solution was stirred at RT for 3 hours, then acidified to pH 3 with 1 N HCl and extracted with (3×250 mL) EtOAc. The combined EtOAc layer was washed with 50 mL water, 50 mL brine, dried over Na2SO4, filtered and concentrated to give 7.09 g (88%) of the title product as clear oil. LRMS (ESI) m/z 244 [(M+H)+; calcd for C12H22NO4: 244].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[CH:20][CH:19]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccc(F)cc4)n3c2c1
Reactant: c1c[nH]cn1
Product: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccc(-n5ccnc5)cc4)n3c2c1

Procedure:
The title compound was prepared as described for Example 21, using 3-cyano-1-(4-fluoro-benzoyl)-8-methyl-pyrrolo[1,2-a]quinoline (54 mg, 0.164 mmol) and imidazole, and yielded 50.1 mg (81%). 1H NMR (CDCl3): 8.20 (dt, J=8.7, 2.1 Hz, 2H), 8.04 (s, broad, 1H), 7.89 (m, 1H), 7.74 (m, 2H), 7.62 (m, 3H), 7.44 (m, 2H), 7.43 (s, broad, 1H), 7.39 (dd, J=7.8, 0.6 Hz, 1H), 7.30 (s, broad, 1H), 2.54 (s, 3H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[O:19])[N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[O:19])[N:10]=[N:9]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCCCc2cn(Cc3ccccc3)nn2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCCCc2c[nH]nn2)CC1

Procedure:
Tert-butyl 4-(6-(1-benzyl-1H-1,2,3-triazol-4-yl)hexanamido)piperidine-1-carboxylate (187 mg, 0.410 mmol) was dissolved in ethanol (10 ml) to give a yellow solution. The solution was then submitted to continuous flow hydrogenation using H-cube hydrogenation apparatus, at 70° C. and 30 bar hydrogen pressure for 2 hours. The resultant solution was concentrated under reduced pressure to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.CC(C)([O-:35])C.[K+].C(OC)(=O)CO>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:7]([C:8]#[N:9])=[C:2]([OH:35])[N:3]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Reactant: CC(C)(C)[O-]
Agent: COC(=O)CO
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(O)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Temperature: 25 °C

Procedure:
400 mg (0.82 mmol) of the compound from Example 4A are initially charged in 8 ml of dry DMF. After addition of 110 mg (0.99 mmol) of potassium tert-butoxide, the mixture is stirred at RT for RT. A solution of 74 mg (0.82 mmol) of methyl glycolate in 1 ml of dry DMF is then added dropwise, and the reaction mixture is stirred at RT for 20 h. The solvent is then removed on a rotary evaporator and the residue is directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[NH2:3].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:2]([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[N:3]=1)([CH3:18])([CH3:17])[CH3:10]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccncc1
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Yield: 16.9 %

Procedure:
Following the procedure in Example 161A Step 3, 4-hydrazinopyridine hydrochloride (1.0 g, 6.87 mmol) and 4,4-dimethyl-3-oxopentanenitrile (860 mg, 6.87 mmol) were reacted to give 3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-amine (250 mg, 1.16 mmol, 17%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (br s, 2H), 7.69 (br s, 2H), 5.55 (br s, 2H), 5.46 (s, 1H), 1.22 (s, 9H); LC-MS (ESI) m/z 217 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH:21]=[CH:22][N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=3)[C:14]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:13]2=3)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>C(O)(C)C>[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][CH2:22][N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=3)[C:14]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:13]2=3)(=[O:10])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])CCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
NaBH4 (46 mg, 2.5 equiv.) was added in small portions to a suspension of 14 (200 mg, 0.48 mmol) and 240 mg of silica (40-60 mesh) in a solution of chloroform and isopropanol (11.6 mL, 8.6:3). The solution was stirred for 1 h 30 at room temperature and then filtered through celite. Solvents were removed under reduced pressure and the crude product was purified by flash chromatography (CH2Cl2/PE 7:3) to afford 15 in 73% yield as a white solid, 1H-NMR (300 MHz, CDCl3): δ 8.49 (d, 1H, J=1.2 Hz), 8.41 (d, 1H, J=8.6 Hz), 8.14-8.10 (m, 3H), 7.74 (bs, 1H), 7.55 (t, 1H, J=7.5 Hz), 7.45-7.40 (m, 3H), 4.70 (t, 2H, J=7.1 Hz), 3.46 (t, 1H, J=7.1 Hz), 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 149.0 (C), 145.8 (CH), 138.4 (C), 137.7 (C), 134.3 (CH), 131.9 (C), 129.9 (CH), 129.2 (2 CH), 128.2 (CH), 127.7 (2C), 122.3 (C), 121.0 (CH), 119.4 (C), 115.7 (CH), 76.4 (CH2), 33.2 (CH2), MS (ESI) m/z 416 [M+H+]
Reaction SMILES: C1(=O)C=CC(=O)C=C1.[Cl:9][SiH:10]([CH3:12])[CH3:11].[C:13]([O:18][CH2:19][CH:20]=[CH2:21])(=[O:17])[C:14]([CH3:16])=[CH2:15]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:13]([O:18][CH2:19][CH:20]=[CH2:21])(=[O:17])[C:14]([CH3:16])=[CH2:15].[C:13]([O:18][CH2:19][CH2:20][CH2:21][Si:10]([Cl:9])([CH3:12])[CH3:11])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C[SiH](C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: C=CCOC(=O)C(=C)C
Agent: O=C1C=CC(=O)C=C1
Product: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of 40 milligrams of hexachloroplatinic acid and 1.0 gram of benzoquinone in 25 grams of allyl methacrylate was heated under anhydrous conditions in an oil bath to 60° C. Chlorodimethylsilane (24 milliliters) was then added slowly by a syringe. The hydrosilylation reaction was exothermic and the chlorodimethylsilane was added at a rate to maintain the temperature of the reaction between 58° C. and 62° C. Distillation of the reaction mixture afforded 4.8 grams of allyl methacrylate and 28.6 grams (81 percent yield based on recoverd starting material) of 3-(chlorodimethylsilyl)propyl methacrylate (bp 82° to 83° C. 0.5τ). This product was characterized by 1H NMR (CDCl3) δ0.34, s, 6H, SiCH3 ; 0.61 to 0.89, m, 2H CH2Si; 1.58 to 1.91, m, 5H, CH2CH3 ; 3.89 to 4.13, t, 2H, CH2 ; 5.52 to 5.35, t, 1H, vinylic; 5.89 to 6.07, t, 1H, vinylic.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[C:6]([Cl:12])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]>>[ClH:12].[CH3:8][C:7]([CH3:10])([CH3:9])[C:6](=[O:11])[S:5][CH2:4][CH2:3][NH2:2]
Reactant: NCCS
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Product: CC(C)(C)C(=O)SCCN
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of cysteamine hydrochloride (30.81 mmol) in pivaloyl chloride (10 mL) was heated to 100° C. during 15 minutes. The reaction mixture was allowed to cool down to room temperature and was triturated in Et2O. The mixture was filtered. The solid was washed with Et2O and then dissolved in DMF (50 mL and 5 drops of HCl) upon heating. After cooled down to room temperature, the mixture was precipitated with Et2O, filtered and washed with Et2O to give after drying under vacuum the expected compound as a white solid in 94% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.19 (s, 9H), 2.88 (t, J=7.08 Hz, 2H), 3.05-3.08 (m, 2H), 8.30 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[CH3:9]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CO.S([O-])(O)(=O)=O.[K+]>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc[nH]1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A suspension of 1H-pyrrole-2-carboxylic acid (5.5 g, 49.5 mmol), WSCI.HCl (12.2 g, 63.6 mmol), HOBt (8.4 g, 62.2 mmol), methanol (7.0 g, 218 mmol) and 4-dimethylaminopyridine (3.0 g, 24.5 mmol) in dimethylformamide (60 ml) was stirred for 70 hours at room temperature and for 2 hours at 60° C. To the reaction mixture was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate/toluene (1/1). The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:1→3:1) to give the subject compound (4.88 g, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][O:11][C@@H:12]([C:29](=[O:34])[N:30]([O:32][CH3:33])[CH3:31])[C@@H:13]([NH:21]C(OC(C)(C)C)=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36].O1CCOCC1>>[ClH:36].[CH2:1]([O:8][C:9](=[O:35])[CH2:10][O:11][C@@H:12]([C:29](=[O:34])[N:30]([O:32][CH3:33])[CH3:31])[C@@H:13]([NH2:21])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)[C@H](OCC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CON(C)C(=O)[C@H](OCC(=O)OCc1ccccc1)[C@@H](N)Cc1ccccc1

Procedure:
(1R,2S)-[2-tert-Butoxycarbonylamino-1-(methoxy-methyl-carbamoyl)-3-phenyl-propoxy]-acetic acid benzyl ester (170 mg, 0.35 mmol) was dissolved in 4N HCl-dioxane (2 mL) for 1.5 hours at 25° C., concentrated, the residue coevaporated with ether and dried giving an oil (163 mg). MS 387 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:15]2[CH2:16][CH2:17][CH:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][CH2:14]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(S(=O)(=O)c3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
The product of step 3 was used in a reductive amination with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure of Example 2 step a.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[NH:41]1[CH:45]=[CH:44][C:43](B(O)O)=[N:42]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[CH:43][NH:42][N:41]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: OB(O)c1cc[nH]n1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cc[nH]n3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Yield: 28.2 %

Procedure:
A similar procedure as described in Example 40, step 7 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (150 mg, 0.22 mmol), 1H-pyrazol-3-ylboronic acid (51.4 mg, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (50.8 mg, 0.04 mmol), and potassium carbonate (30.2 mg, 0.22 mmol) to afford 4-(2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-methanesulfonyl-5-(1H-pyrazol-3-yl)-phenoxy]-hexyl}-phenoxy)-butyric acid ethyl ester (39 mg, 28.5%) as a light brown viscous oil: ES(+)-HRMS m/e calcd for C33H44N2O8S (M+H)+ 629.2891, found 629.2894.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:35]1[S:36][CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: Cc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)cs1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (855 mg; compound B50) is reacted with 4-(chloromethyl)-2-methyl-1,3-thiazole (295 mg; compound D10) in the presence of potassium carbonate (276 mg) in DMF (15 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:39])([F:38])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]2[CH2:29][CH:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:26]2)=[O:24])=[CH:18][CH:17]=1.[CH:40](OC)=[O:41]>O1CCCC1.CCCCCC.C(O)(=O)C>[F:39][C:14]([F:13])([F:38])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]2[CH2:29][C:28]([CH:40]=[O:41])([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:26]2)=[O:24])=[CH:18][CH:17]=1
Reactant: COC=O
Reactant: CC1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C=O)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To 3.5 ml of diisopropylamine dissolved in 20 ml of tetrahydrofuran and cooled in a -20° C. bath was added 10.0 ml of a 2.5 molar solution n-butyllithium in hexane. After stirring for 5 minutes a solution of 4.0 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide in 10 ml of tetrahydrofuran was added and the resulting solution stirred for 15 minutes and then cooled to -78° C. To this solution was added 2.0 ml of methyl formate and, after 5 minutes, 2 ml of acetic acid was added. The reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered, evaporated in vacuo to give 3.9 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-formyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR and IR data were consistent with the structure.