Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][NH:13][CH2:14]2)[CH2:10][CH2:9]1)=[O:6].C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>ClCCl>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][N:13]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=3)(=[O:40])=[O:39])[CH2:14]2)[CH2:10][CH2:9]1)=[O:6]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCOCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-4-Methyl-2-morpholino-N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)pentanamide (191 mg, 0.617 mmol), triethylamine (0.129 mL, 0.926 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.109 mL, 0.679 mmol) were combined in dichloromethane (0.5 mL). The reaction was stirred at room temperature for 3 hours. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=6.2, 1H), 8.38 (s, 1H), 8.19 (d, J=7.9, 1H), 7.92 (d, J=7.8, 1H), 7.72 (t, J=7.9, 1H), 4.27-4.20 (m, 1H), 3.90 (dd, J=2.3, 10.0, 1H), 3.76-3.67 (m, 4H), 3.20 (ddd, J=3.9, 9.4, 10.9, 3H), 2.97 (dd, J=7.1, 9.6, 1H), 2.78-2.72 (m, 2H), 2.72-2.67 (m, 2H), 2.62-2.53 (m, 2H), 1.94 (dt, J=6.2, 12.1, 1H), 1.89-1.77 (m, 3H), 1.64-1.54 (m, 2H), 1.30 (ddt, J=6.5, 9.3, 12.8, 1H), 0.92 (d, J=4.4, 3H), 0.91 (d, J=4.4, 3H); MS (ESI+) m/z 518(M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28](OC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13]
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)N1C(=O)NC(COC)=C(C(=O)OC)[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
β-Alanine ethyl ester hydrochloride (87 mg, 0.57 mmol), (+)-5-methyoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6 (S)-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine (as described in Section I.A.(c)) (227 mg, 0.48 mmol), and triethylamine (209 mL, 1.50 mmol) were combined in 5 mL of dichloromethane. The yellow mixture was stirred at ambient temperature for 1 hour, then evaporated to dryness. The resulting oil was purified by “flash” chromatography (5.02, 98:2:0.2 of dichloromethane: methanol:ammonium hydroxide). The product fractions were evaporated to dryness to give the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)O)=[CH:4][CH:3]=1.P(Cl)(Cl)[Cl:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)[Cl:21])=[CH:4][CH:3]=1
Reactant: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3)cc21
Reactant: ClP(Cl)Cl
Product: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21

Procedure:
The alcohol (d) is reacted with phosphorus trichloride, yielding the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:13]1[CH2:18][CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1>>[O:13]1[CH2:14][CH:15]=[C:16]([C:2]2[C:3]3[N:4]([N:9]=[C:10]([NH2:12])[N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:17][CH2:18]1
Reactant: Cc1cc(Br)c2nc(N)nn2c1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: Cc1cc(C2=CCOCC2)c2nc(N)nn2c1

Procedure:
Prepared in analogy to example 160b, starting from 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The title compound was obtained a light brown solid (yield: 55%) after column chromatography on silica gel using ethyl acetate as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Cl)=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22])=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccc(Br)cc2)n1
Reactant: COCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNc1nc(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 35.4 %

Procedure:
To a solution of 1-(4-bromophenyl)-5-chloro-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazole (Intermediate-3, 0.100 g, 0.257 mmol) in DMF (3.0 mL) was added 3-methoxypropan-1-amine (0.035 g, 0.386 mmol) and DIPEA (1.0 mL). The reaction mass was stirred at 80° C. for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.040 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.92 (d, J=5.4 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 3.28 (s, 3H), 3.56-3.64 (m, 2H), 5.69 (m, 1H), 7.06-7.15 (m, 1H), 7.22-7.49 (m, 2H), 7.54 (d, J=10.2 Hz, 2H), 7.64 (d, J=8.4 Hz, 21-1). MS (m/z): 441.19 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A mixture of 1.35 g of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde and 0.84 g of sodium borohydride in 10 ml of methanol was stirred at room temperature for 30 minutes. Water (10 ml) was added and the mixture was extracted four times with 15 ml of diethyl ether. Combined extracts were dried over magnesium sulphate, filtered and evaporated to leave 670 mg of [5-(3,5-dichloro-phenylsulphanyl)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-methanol as a grey paste which was used without further purification. Mass spectrum (ES) m/z 365 [M+H]+, 406 [M+H+CH3CN]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]2=[N:15][C:14]=1[CH3:28].C1COCC1.[Li]C(C)(C)C.[F:39]NS(C1C=CC=CC=1)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[C:10]([F:39])[N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:16]2=[N:15][C:14]=1[CH3:28]
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nc(F)nn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 22.2 %

Procedure:
To a −78° C. solution of 3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 0.72 mmol) and THF (8 mL) is added 1.7 M tert-BuLi (0.47 mL, 0.80 mmol). After 30 minutes the solution is transferred via a cannula into a solution of N-fluorobenzenesulfonamide (0.40 g, 1.25 mmol) and THF. After 30 minutes the solution warmed to ambient temperature. The solution is diluted with EtOAc (40 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The solution is purified by ISCO (20%-30% EtOAc gradient) furnish the title compound (0.068 g, 0.16 mmol, 16%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.71-1.93 (m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.26-3.36 (m, 1H), 4.08 (d J=2.7 Hz, 3H), 6.75 (s, 1H), 7.97 (s, 1H). LC/MS (m/z): calcd. for C20H22ClFN6S (M+H)+: 433.2; found: 433.2.
Reaction SMILES: CC1(C)C2[CH:10]=[C:9]([C:12](=[O:30])[CH:13]=[CH:14][C:15]3[CH:29]=[CH:28][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7]C=2C(C2C=CC(C)=CC=2)=CC1.[CH3:39][C:40]1([CH3:59])[C:48]2[C:43](=CC=C(C(=O)C)C=2)[C:42]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)=[CH:41]1>>[CH3:39][C:40]1([CH3:59])[C:48]2[C:43](=[CH:7][CH:8]=[C:9]([C:12](=[O:30])[CH:13]=[CH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])=[O:20])=[CH:28][CH:29]=3)[CH:10]=2)[C:42]([C:52]2[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=2)=[CH:41]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)C=C2c1ccc(C)cc1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4)ccc32)cc1
Product: Cc1ccc(C2=CC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4)ccc32)cc1
Yield: 25 %

Procedure:
Following a procedure similar to that for the preparation of 2-trimethylsilanyl-ethyl 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-naphthalen-2-yl)-3-oxo-propenyl]-benzoate (Compound 6) while using 1-(3,3-dimethyl-1-p-tolyl-3H-inden-5-yl)-ethanone (Compound 14, 200 mg, 0.72 mmol) as the starting material yielded the title compound (93 mg, 25% yield) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1Cc2ccccc2CN1
Product: CC1Cc2ccccc2CN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1.C1(C)C=CC=CC=1.[CH3:34][CH2:35][O-:36].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C:12]#[N:13])=[C:14]([O:36][CH2:35][CH3:34])[CH:15]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1
Reactant: CC[O-]
Reactant: CC(C)[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(N)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cc(N3CCOC[C@H]3C(C)C)nc(N)n2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (405 mg, 1.12 mmol) was azeotroped with toluene (2×15 mL). The residue was dissolved in 5 mL of DMF as a yellow clear solution, to which was added NaOEt (1.45 mL of a stock solution with concentration of 0.87 mmol/mL, 1.25 mmol, 1.12 equiv) at room temperature in one portion. The resulting light orange clear solution was stirred at room temperature for 20 hours. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, providing the title compound (310 mg) as a white solid residue. LC-MS (ES) m/z=386 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: CCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added heptanoyl chloride (0.10 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.10 g (74%) of product as an off-white solid: mp 172-174° C.; 1H NMR (DMSO-d6) 11.05 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.77-2.43 (m, 5H), 2.08-2.03 (m, 1H), 1.90 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 172.12, 172.02, 168.74, 167.36, 136.41, 135.90, 131.20, 125.70, 117.71, 116.31, 58.81, 36.51, 30.93, 29.07, 28.54, 28.12, 24.69, 21.94, 20.98, 13.86; Anal. Calcd. For C21H21N3O5: C, 62.83; H, 6.33; N, 10.47 Found: C, 62.45; H, 6.18; N, 10.24+0.50H2O.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=[C:11]([CH2:20]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:36]([CH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=1)=[N+:37]=[N-:38]
Reactant: CC1(C)Oc2cc(CO)cc(OCc3ccccc3)c2O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC1(C)Oc2cc(CN=[N+]=[N-])cc(OCc3ccccc3)c2O1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of (7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-methanol (0.57 g, 2.0 mmol) and diphenylphosphoryl azide (0.52 mL, 2.4 mmol) in tetrahydrofuran (10 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.33 mL, 2.2 mmol). The mixture is allowed to warm to room temperature over the weekend and then quenched with the addition of water. The reaction mixture is extracted 3× with ethyl acetate, and the combined extracts were washed with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to give 6-azidomethyl-4-benzyloxy-2,2-dimethyl-benzo[1,3]dioxole, which is used in the next step without purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:30][OH:31].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:31][NH:30][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC)c(OC)c3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(c3ncc(C(=O)NO)s3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12b) (125 mg, 0.292 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (202 mg, 2.92 mmol) and a freshly prepared solution of sodium methoxide in methanol (100 mg, 4.35 mmol of sodium dissolved in 1 mL of methanol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13b as a solid. HPLC: 86.09% (Rt=12.51 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4](C(Cl)(Cl)Cl)[N:3]=1.[CH3:15][O-:16].[Na+].O>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([O:16][CH3:15])[N:3]=1
Reactant: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1.33 h

Procedure:
25.3 g of 2-amino-4-cyclopropyl-6-trichloromethyl-1,3,5-triazine are added to a solution of 10.8 g of sodium methylate in 50 ml of methanol, and the mixture is stirred at 60° C. for 80 minutes. There are added 300 ml of water, and the formed suspension is filtered. The filter residue is suspended twice in 100 ml of acetyl acetate each time, and again filtered. The organic phases are collected, dried over magnesium sulfate and concentrated by evaporation to thus obtain an oil, which crystallises when stirred up in ether. The yield is 6.7 g of the title compound, m.p. 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=1[F:18].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([F:18])[CH:13]=2)[CH:7]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: Fc1ccc(I)cc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1F
Temperature: 60 °C
Yield: 85.5 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (49 mg, 0.07 mmol), copper (I) iodide (28 mg, 0.15 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (200 mg, 1.5 mmol) to a solution of 1,2-difluoro-4-iodobenzene (420 mg, 1.7 mmol) in triethylamine (3.1 mL, 22 mmol) and heat at 60° C. for 16 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 50:50 to 100:0 dichloromethane:hexanes, followed by a second silica gel chromatography, eluting with 95:5 to 85:15 hexanes:ethyl acetate to give the title compound as a white solid (320 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([CH3:27])([CH3:26])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([NH:19][S@@](C(C)(C)C)=O)[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.[ClH:29]>CO.O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C:4]([CH3:27])([CH3:26])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([NH2:19])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N[S@](=O)C(C)(C)C)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-2,2-dimethyl-4-{2-[(R)-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-quinolin-7-yl}-but-3-enoic acid methyl ester (700 mg, 1.74 mmol) in methanol (20 mL) was treated with hydrochloric acid in 1,4-dioxane (4 M, 10 mL). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residual solvent was azeotroped off with toluene (3×15 mL) to give crude (E)-4-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid methyl ester hydrochloride.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:19][C:20]1[N:25]=[C:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(I)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)n2)c1

Procedure:
The title compound was prepared from 2-iodo-4-methyl-6-(4-trifluoromethyl-phenyl)pyridine (example A.58) (2.55 g, 7.0 mmol), i-PrMgCl/ZnCl2 and commercially available 2,4-dichloropyrimidine (1.08 g, 7.21 mmol) according to the general procedure IVc protocol b. Obtained as a light brown solid (0.896 g, 37%). MS (ISP) 350.3 [(M+H)+] and 352 [(M+2+H)+].
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCCC(C=O)=CC=Cc1ccccc1
Agent: [Ni]
Product: CCCC(CO)CCCc1ccccc1
Reaction time: 20 h
Yield: 89.7 %

Procedure:
395 g of 5-Phenyl-2-n-propyl-penta-2,4-dienal from Synthesis Example 1.1 were combined with 14 g of Raney-Ni and hydrogenated at a hydrogen pressure of 20 bar and at a temperature of 120° C. After 20 hours the reaction was finished. The catalyst was removed and the product distilled. 365 g (content 96%) of 5-phenyl-2-n-propyl-pentanol are obtained. Yield: 93.6% of theoretical.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C.C1COCC1>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Add potassium tert-butoxide (2.69 g, 24 mmol) to a 0° C. solution of 3-hydroxy-pyridine (1.90 g, 20 mmol) in DMF (30 mL) and THF (30 mL) stirring under N2. Add 2-(trimethylsilyl)ethoxy-methyl chloride (3.72 mL, 21 mmol) dropwise and allow to warm slowly to RT overnight. Add water to quench, stir for 5 minutes and concentrate. Dissolve in 20% i-PrOH/CHCl3, wash with saturated NaHCO3 solution (2×) and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-50% EtOAc/hexanes to afford the title compound (3.14 g, 70%) as yellow liquid. MS(IS) 226 (M+1). TLC: Rf=0.43 (50% EtOAc/hexanes).