Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[NH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([NH:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(NC1Cc2ccccc2C1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 8.8 g (66.0 mmol) of 2-aminoindan. The reaction mixture was refluxed for four hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using chloroform as eluent and was concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a tan, viscous oil. MS (ion spray) 282.2 (M+).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:31])[NH:21][C:22]3[S:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][N:26]=3)=[CH:16][C:15]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[S:23][C:24]([C:27]([CH3:28])([CH3:29])[CH3:30])=[N:25][N:26]=3)=[O:31])=[CH:16][C:15]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 181B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The resultant residue was purified by silica gel chromatography eluting with 4% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 1.41 (s, 9 H) 3.16-3.30 (m, 1 H) 5.64 (s, 1 H) 6.65 (d, J=8.46 Hz, 2 H) 6.85 (d, J=8.46 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.46 Hz, 1 H) 7.94 (dd, J=8.46, 1.84 Hz, 1 H) 8.10 (d, J=1.47 Hz, 1 H) 8.59 (s, 1 H) 8.89 (d, J=8.82 Hz, 1 H) 10.15 (s, 1 H) 12.85 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.P(Br)(Br)([Br:25])=O>BrCBr>[Br:25][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)C(O)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: BrCBr
Product: CC(C)C(Br)c1cnc(Cl)nc1Cl
Reaction time: 0.17 h

Procedure:
(±)-1-(2,4-Dichloro-pyrimidin-5-yl)-2-methyl-propan-1-ol (0.18 g; 0.83 mmol) (from Example 11a supra) was combined with N,N-diisopropyl-ethylamine (0.37 mL; 2.10 mmol) (Aldrich) and a small volume of dibromomethane (50 μL) (Aldrich) to help solubilize the mixture. Only a small amount of material remained insoluble. Neat phosphorus oxybromide (0.22 g; 0.85 mmol) (Aldrich) was added in one portion. Reaction mixture was stirred for 10 minutes and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M) gave (±)-5-(1-bromo-2-methyl-propyl)-2,4-dichloro-pyrimidine as a colorless oil. (Yield 79.5 mg; 33.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:14]([C@@H:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@@H:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:23][C@@H:22]1[OH:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Reactant: O[C@H]1CNCC[C@H]1Cc1ccccc1
Product: O=S(=O)(CCN1CC[C@@H](Cc2ccccc2)[C@@H](O)C1)c1ccc(O)cc1
Yield: 50 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3R,4R)-4-benzyl-piperidine-3-ol in 50% yield as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][N:22]([CH3:31])[N:21]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.FC1C=C(O)C=CC=1C1C(C2C=CN=CC=2)=CN(C[C:51]([F:54])([F:53])[F:52])N=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][N:22]([CH2:31][C:51]([F:54])([F:53])[F:52])[N:21]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Solvent: CC(C)=O
Product: Fc1cc(OCc2ccc3ccccc3n2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[3-Fluoro4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 3-Fluoro4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol and acetone as the solvent provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (m, 2 H), 7.80 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.24 (m, 5 H), 6.72 (dd, J=8.3, 2.5 Hz, 1 H), 6.50 (dd, J=11.6, 2.1 Hz, 1 H), 4.81 (q, J=8.4 Hz, 2H); MS: (M+H m/z=479.2).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1.N1C=CC=NC=1C1C=C(C=CC=1)C(O)=O.Cl.CCOCC.[C:38]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH3:39].[Li]>CO>[C:42]([O:41][C:38](=[O:40])[CH2:39][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:5]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)c1cccc(-c2ncccn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)c1cccc(-c2ncccn2)c1
Agent: [Li]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1

Procedure:
The title compound was prepared from 3-pyrimidin-2-yl-benzoic acid methyl ester [prepared by the following procedure: 3-Pyrimidin-2-yl-benzoic acid (3.0 g) was esterified by heating in MeOH (160 ml)/4N HCl-Et2O (40 ml) for 16 h at 40° C.; white crystals (1.99 g).] (1.99 g, 9.3 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (3.24 g, crude product).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=1[O-:29].C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=2[O-:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])c(NCCCOc2cccc(CN3CCCCC3)c2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (6.21 g), 2-chloro-4-nitropyridine-N-oxide (4.36 g) and triethylamine (6.32 g) were stirred, in ethanol (30 ml), under reflux for 31/2 hours. The reaction mixture was cooled gradually to 0° C. to yield 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-nitropyridine-N-oxide (4.23 g), m.p. 90°-90.5° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[ClH:26].O>O1CCOCC1>[Cl:26][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCCl)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 2 h

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) was dissolved in dioxan (40 ml) and dry hydrogen chloride passed through the solution for 1 hour. The mixture was left to stand for a further 2 hours, then poured into water and the sticky solid extracted into ether. The extracts were washed with saturated sodium bicarbonate, water and then dried over anhydrous sodium sulphate. After evaporation and trituration of the resulting foam with ether/petrol the title compound (375 mg) was obtained as a white solid. m.p. 110°-112° with gas evolution [α]D + 100° (c = 1.06).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(C#N)cc3)CCC2)cc1
Yield: 86.7 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 500 mg (1.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 540 mg (3.7 mmol) of 4-cyanophenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (19:1) gave 480 mg (89%) of 1-[2-(4-cyanophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as an oil: NMR (CDCl3) d 2.07 (m, J=7 Hz, 2H) , 2.42 (s, 3H) , 2.89 (t, J=7 Hz, 4H) , 7.05 (d, J=8 Hz, 2H) , 7.11 (d, J=8 Hz, 2H) , 7 . 26 (d, J=8 Hz, 2H) , 7.48 (d, J=8 Hz, 2H ) .
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](Cl)(=[O:26])=[O:25])([O:17][CH3:18])=[O:16]>C1COCC1>[CH3:18][O:17][C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](=[O:26])(=[O:25])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of an aniline (1.02 g, 10.9 mmol, 11.1 equivalents) dissolved in dry THF (35 mL) and triethylamine (1.53 mL, 1.1 equivalents) at room temperature, sealed with a septum and a nitrogen inlet, was added 2-carbomethoxythiophene-3-sulfonyl chloride (2.5 g, 9.9 mmol, 95% purity). The reaction mixture was stirred at room temperature over night. Upon completion, the reaction will be extracted by diluting with ethyl acetate and washing with aqueous HCl (2N), water and saturated, aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The solution will be decanted and evaporated under reduced pressure to give the desired 3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester (2.6 g, 88%).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[S-:11][C:12]#[N:13].[NH4+].C(O)C>O>[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:12]([NH2:13])=[S:11]
Reactant: N#C[S-]
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1NNC(N)=S

Procedure:
A mixture of 15.9 g. (0.1 moles) of o-tolylhydrazine hydrochloride, 15.2 g. (0.2 moles) of ammonium thiocyanate, 300 ml. of ethanol and 30 ml. of water are heated at reflux temperature for 24 hours, the solvent is removed by distillation at atmospheric pressure, and sufficient water added to cause precipitation. The aqueous suspension is filtered and the solid residue recrystallized from aqueous ethanol affording 15 g. (85%) of 1-(o-tolyl)-3-thiosemicarbazide, m.p. 158°-160° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:26][C:27]1[O:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[N:29][C:28]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:28]4[N:29]=[C:30]([C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[O:31][C:27]=4[CH3:26])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, 1H, J=3.90 Hz, J=1.47 Hz), 7.35 (dd, 1H, J=5.37 Hz, J=1.47 Hz), 7.13 (d, 2H, J=8.31 Hz), 7.04 (dd, 1H, J=5.37 Hz, J=3.90 Hz), 6.78 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.30 Hz), 6.42 (d, 1H, J=2.44 Hz), 6.33 (dd, 1H, J=8.31 Hz, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.15 (t, 2H, J=6.35 Hz), 3.16 (d, 1H, J=13.92 Hz), 3.04 (d, 1H, J=13.92 Hz), 2.93 (t, 2H, J=6.35 Hz), 2.31 (s, 3H), 1.30 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H26NO7S 508.1430, found 508.1425.
Reaction SMILES: [OH-].[Li+].C[C@H]1[C@H](C2C=CC=CC=2)OC(=O)N1[C:16](=[O:27])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH3:18].C(OCC)(=[O:30])C>O1CCCC1.O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:17]([CH3:18])[C:16]([OH:27])=[O:30]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reactant: CCOC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
1.52 g of lithium hydroxide are added to a solution, cooled to +5° C., of 4.1 g of (4S,5S)-4-methyl-5-phenyl-3-[2-(2-methoxyphenyl)-(S)-propionyl]-oxazolidin-2-one in 60 cm3 of tetrahydrofuran and 30 cm3 of water. The reaction mixture is stirred at this temperature for 3 hours and, after returning to room temperature, ethyl acetate is added, the mixture is decanted, the aqueous phase is acidified with an aqueous 1N solution of hydrochloric acid and extracted with ethyl acetate, and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallised from hexane, filtered off and dried. 0.4 g of (S)-2-(2-methoxyphenyl)-propionic acid is obtained in the form of white crystals which melt at 102° C. [α]D20 =+84.6° (c=1; CHCl3).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.CC(C)([O-])C.[Na+]>CS(C)=O.O>[O:11]1[CH2:12][CH:13]=[C:8]([C:7]2[C:2]([O:14][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Clc1ncccc1C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-pyridine (see PREPARATION P13.1; 3.5 g, 17.9 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.8 g, 17.9 mmol) were dissolved in DMSO (20 mL) and sodium tert-butoxide (t-BuONa) (3.4 g, 35.8 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crud product was purified by silica gel column chromatography to give the title compound (2.3 g, 7.8 mmol, yield 75%). 1H NMR (DMSO-D6, 300 MHz) δ (ppm) 1.38 (s, 9H), 2.41-2.47 (m, 2H), 3.75-3.86 (m, 4H), 4.19-4.30 (m, 4H), 5.26-5.35 (m, 1H), 6.15-6.20 (m, 1H), 7.01 (dd, 1H, J=7.31 Hz, 4.97 Hz), 7.62 (d, 1H, J=7.45 Hz), 8.02 (d, 1H, J=4.82 Hz)
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46](C(OC(C)(C)C)=O)[CH:47]=2)O1>O>[CH3:12][C:6]1([CH3:13])[N:5]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[N:45][NH:46][CH:47]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1CC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)cc2N1CC(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
A flask was charged with 6-bromo-2,2-dimethyl-1-(2-(morpholin-4-yl)-2-oxoethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (115 mg, 0.296 mmol), Na2CO3 (89 mg, 1.48 mmol), 1,2-dimethoxyethane (2 mL), water (1 mL) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (261 mg, 0.888 mmol). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (24 mg, 0.0296 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 3 h, water and EtOAc were added to quench the reaction. The insoluble materials were filtered off, and NaCl was added to the filtrate. The organic materials were extracted with EtOAc/THF, and the extract was concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (31 mg, 27%) as a pale brown solid:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[OH:9].Br[C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17].O>CN(C)C=O>[CH3:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[O:9][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: Cc1oc2ccccc2c1O
Reactant: COC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1c(C)oc2ccccc12
Reaction time: 0.25 h

Procedure:
To a suspension of 9 g of sodium hydride (50 percent in oil) in 150 ml of anhydrous dimethylformamide were added drop-by-drop and while stirring 22.2 g (0.15 mol) of 2-methyl-3-hydroxy-benzofuran, care being taken to maintain the temperature at about 30°-35°C. The reaction medium was stirred for a further 15 minutes and then 27.2 g (0.15 mol) of methyl α-bromoisobutyrate were added, the temperature being maintained at 35°-40°C. Stirring was continued for 24 hours at room temperature, the reaction mixture was poured into water and extracted several times with ether. The ethereal extracts were collected, washed with water and dried over anhydrous sodium sulphate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8]N)[N:3]=1.CCO.[CH3:13][C:14]([CH2:16][CH3:17])=O>C(O)COCCO>[Br:1][C:2]1[N:3]=[C:4]2[NH:8][C:14]([CH3:13])=[C:16]([CH3:17])[C:5]2=[CH:6][CH:7]=1
Reactant: NNc1cccc(Br)n1
Reactant: CCC(C)=O
Solvent: CCO
Solvent: OCCOCCO
Product: Cc1[nH]c2nc(Br)ccc2c1C
Yield: 15.7 %

Procedure:
A suspension of 2-bromo-6-hydrazinopyridine (32,5 g, 0.17 mol) in abs EtOH was treated with ethyl methyl ketone (20 ml, 0.22 mol) for 1 h at reflux. The reaction mixture was allowed to cool and treated with additional ethyl methyl ketone (10+3+1 ml) until all starting material had dissapeared according to TLC. The reaction mixture was taken up in 150 ml diethylene glycol and the EtOH evaporated at reduced pressure at 70° C. The remaining solution was deaerated and heated to reflux for 22h. The reaction mixture was cooled and paritioned between 1250 ml CH2Cl2 and 1000 ml 2M HCl (reextracted with 250 ml CH2Cl2). The organic layer was washed with further 500 ml 2M HCl and 500 ml H2O dried over MgSO4, and evaporated. Chromatography (silica, CH2Cl2 /diethyl ether; 95/5) afforded 6 g 6-bromo-2,3-dimethyl-pyrrolo[2,3-b] pyridine. Recrystallization from 120 ml abs EtOH gave 4,2 g (11%). (1H-NMR, 500 MHz, CDCl3) 2.19(s,3H), 2.42(s,3H), 7.16(d, 1H), 7.59(d, 1H), 9.12(b, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH:10]([OH:12])[CH3:11]>CC#N>[CH3:11][CH:10]([OH:12])[CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(O)CCCl
Solvent: CC#N
Product: CC(O)CCN1CCOCC1

Procedure:
To 100 mL of CH3CN is added morpholine (9.6 g, 0.11 mol) and 4-chloro-2-butanol (11 g, 0.1 mol). Heat the reaction at reflux and monitor the reaction by thin-layer chromatography. Upon completion of the reaction remove the solvent and add saturated aqueous sodium bicarbonate and ether. Separate the layers and dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[S:29][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:15])=[C:11]([CH3:36])[C:10]=1[C:37]#[N:38])=O)(C)(C)C.[ClH:39]>CO.ClCCl>[ClH:39].[ClH:39].[ClH:39].[NH2:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[S:29][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:27][CH:26]=3)[CH2:22][CH2:23]2)=[O:15])=[C:11]([CH3:36])[C:10]=1[C:37]#[N:38]
Reactant: Cc1c(C(=O)OCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)sc(NC(=O)OC(C)(C)C)c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)OCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)sc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound prepared in Example 223 (0.026 g) was suspended in methanol (2 mL) and dichloromethane (2 mL). Hydrogen chloride solution (4 M in 1,4-dioxane) (3.0 mL) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.027 g), which was used without further purification possessing the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13](N)=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:27]C1C=CC([C@@H](N)C)=CC=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:27])=[CH:12][CH:13]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Product: C[C@H](Nc1ccc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 185 °C
Yield: 26.8 %

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,6-difluoropyridin-2-amine (Method 31, 0.10 g, 0.42 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.2 mmol) were heated to 185° C. under microwave conditions (30 min×3 cycles). The resulting dark oil was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.04 g, 26%). 1H NMR (400 MHz, CD3OD) δ 7.08-6.99 (m, 3H), 6.67-6.62 (m, 2H), 6.22 (dd, J=8.9, 2.3 Hz, 1H), 5.04 (s, 1H), 4.64-4.59 (m, 1H), 1.16-1.12 (m, 4H), 0.30-0.14 (m, 3H), 0.04-0.02 (m, 1H). MS: Calcd.: 355. Found: [M+H]+ 356.