Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Reactant: Fc1ccc([Mg]Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NC(=O)c1cnc(Cl)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
14.1 ml (14.1 mmol) 4-Fluoro-phenylmagnesium chloride solution (1M in THF) were added over 10 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at 35° C. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 20 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After 30 minutes at room, temperature, the brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 5 ml n-hexane/ethyl acetate 4:1 to yield 0.69 g (48%) N-tert.-butyl-6-chloro-4-p-fluoro-phenyl-nicotinamide as a light brown powder of m.p.=168-173° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]4[CH:20]=[C:19]([C:21](O)=[O:22])[NH:18][C:15]4=[CH:16][N:17]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:29]([N:31](CC)[CH2:32][CH3:33])[CH3:30].N1CCCC1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:13]=[C:14]4[CH:20]=[C:19]([C:21]([N:31]5[CH2:32][CH2:33][CH2:30][CH2:29]5)=[O:22])[NH:18][C:15]4=[CH:16][N:17]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.46 g (1.31 mmol) 5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid 0.56 mL (6.6 mmol) oxalylchloride and 0.03 mL DMF in 30 mL DCM was stirred at room temperature for 1 h and evaporated to dryness. An aliquot containing 0.054 mmol of the intermediately built acid chloride was treated with 27 mg (0.27 mmol) triethylamine and 11.6 mg (0.16 mmol) pyrrolidine in 2 mL DCM during 16 h at room temperature. After evaporation of all volatiles the residue was taken up in a mixture of DMF/methanol/water/NEt3 and subjected to preparative HPLC purification on reversed phase eluting with a acetonitrile/water (0.05% NEt3) gradient. After evaporation of the product fractions 4.1 mg (14%) of the title compound was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH2:17][CH2:18][C:19]4[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=4)[N:21]=3)[CH2:12][CH:11]=2)=[CH:2]1.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH2:17][CH2:18][C:19]4[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=4)[N:21]=3)[CH2:14][CH2:15]2)=[CH:2]1
Reactant: FC(F)(F)c1nnc2n1N=C(N1CC=C(c3c[nH]c4ccccc34)CC1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: FC(F)(F)c1nnc2n1N=C(N1CCC(c3c[nH]c4ccccc34)CC1)CC2
Temperature: 78 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
10% Palladium on carbon (23.96 mg, 0.02 mmol) was added to 6-[4-(1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 2) (87 mg, 0.23 mmol) and ammonium formate (71.0 mg, 1.13 mmol) in ethanol (20 mL). The resulting mixture was stirred at 78° C. for 2 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, then re-dissolved in ethyl acetate (25 mL) and the solution washed sequentially with water (20 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 6-[4-(1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (60.0 mg, 69%) as a solid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[OH2:25]>C(O)(=O)CC>[OH:25][C@@H:3]1[C@@H:2]([O:1][C:2](=[O:1])[CH2:3][CH3:4])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CCC(=O)O
Product: CCC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg) was dissolved in propionic acid (10 ml) and the solution heated on a steam bath for 5 hours. The mixture was poured into water (200 ml) and the white precipitate extracted into ether. The ethereal solution was washed with 2N-sodium hydroxide solution until the aqueous layer remained basic, then water and then dried over anhydrous sodium sulphate. The dried solution was evaporated to a white foam (560 mg) which was purified by preparative T.L.C. using ethyl acetate/petrol (2/1). The main band (Rf 0.4-0.5) gave title compound (393 mg.) as a white foam. [α]D + 84.4° (c 1.05).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:30]=[CH:31][C:32]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4C(OC(C)(C)C)=O)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[CH2:38]([N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][C@@H:19]5[CH2:21][C@H:16]4[CH2:17][NH:18]5)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:30]=[CH:31]2)=[N:35]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnn2c(CCCCN3C[C@@H]4C[C@H]3CN4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of tert-butyl (1S,4S)-5-{-4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]butyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in MeOH (1 mL) was added 4M HCl in dioxane (0.5 mL). The mixture was stirred at rt for 2 h. Additional 4M HCl in dioxane (0.5 mL) was added and the mixture continued to stir at rt for 16 h. The mixture was concentrated and the residue was partitioned between saturated, aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 36 mg (62%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.88 (s, 1 H), 7.79 (d, 1 H), 7.57 (s, 1 H), 7.28-7.39 (m, 5 H), 7.13 (d, 1 H), 6.58 (s, 1 H), 5.64 (s, 2 H), 3.51 (s, 1 H), 3.25-3.47 (m, 2 H), 2.97 (d, 1 H), 2.87 (t, 2 H), 2.73 (dd, 1 H), 2.66 (dd, 2 H), 2.37-2.45 (m, 1 H), 2.33 (d, 1 H), 1.59-1.77 (m, 3 H), 1.35-1.52 (m, 3 H); ES-MS m/z 493.27 [M+H]+, HPLC RT (min) 1.89.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH:21][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=2)=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)CCCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCN1CCC(Cc2ccccc2)CC1)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
To a solution of 5-(4-benzylpiperidin-1-yl)valerhydrazide (289 mg, 1.00 mmol) in 10 mL of CH2Cl2 and 0.21 mL of Et3N was added 4-nitrobenzoyl chloride (278 mg, 1.50 mmol). The resulting solution was allowed to stir at rt for 12 hr. The mixture was poured into ice water (10 g). The organic layer was separated and the water phase was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4. Evaporation of solvent gave the title product as a brown oil (405 mg, 92%): 1H NMR (CDCl3) 1.25 (m, 2 H), 1.60 (m, 6 H), 1.90 (m, 2 H), 2.29 (m, 4 H), 2.48 (d, J=6.6 Hz, 2 H), 2.90 (m, 2 H), 3.42 (s, 1 H), 7.07-7.24 (m 5 H), 7.70 (bs, 2 H), 7.96 (d, J=7.8 Hz, 2 H), 8.08 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[OH:9].OO.[O-]S([O-])(=O)=O.[Mg+2]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9]
Reactant: CC1CCCC(C)C1O
Agent: O=S(=O)([O-])[O-]
Agent: OO
Agent: [Mg+2]
Product: CC1CCCC(C)C1=O
Yield: 89 %

Procedure:
Example 3 was repeated, replacing (-)-menthol by 2,6-dimethylcyclohexanol (6.4 g; 50 mmol), using 5.1 cm3 (60 mmol) of 40% of H2O2, adding 4 g of anhydrous MgSO4 and reducing the reaction time to 30 minutes. 5.61 g (44.5 mmol) of 2,6-dimethyl-cyclohexanone were obtained (GLC purity>99%), which corresponds to a 89% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:32]([C:29]3[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=3)(=[O:34])=[O:33])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NCc3ccccc3)ccc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)n1
Temperature: 25 °C

Procedure:
A solution of 6-Benzylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (320 mg, 0.95 mmol), methyl-1-H-pyrazole-3-sulfonyl chloride (303 mg, 1.68 mmol) and pyridine (229 μl, 2.84 mmol) in dry dichloromethane (10 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as an off yellow solid (393 mg, 86% yield). HPLC retention time 4.72 min. Mass spectrum (ES+) m/z 505 (M+23, sodium salt).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1>C(O)CCC>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([O:1][CH2:2][CH2:7][CH2:6][CH3:11])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C

Procedure:
A suspension of powdered 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carbonyl chloride (5.0 g.) in n-butanol (100 ml.) was heated on a steam bath for 30 minutes. The solution was cooled to ambient temperature, and the solvent was evaporated under reduced pressure. The sticky solid residue was triturated with petroleum ether (b.p. 60°-80° C.), filtered, washed with petroleum ether and crystallised from n-butanol to give butyl 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carboxylate, m.p. 134°-136° C.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[CH:19][CH:18]=2)[CH:13]=1)=S)[CH:6]([CH3:8])[CH3:7].IC.Cl.[NH2:38][OH:39].C([O-])(O)=O.[Na+]>CO>[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[CH:19][CH:18]=2)[CH:13]=1)=[N:38][OH:39])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@@H](NC(=S)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)[C@@H](NC(=NO)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of freshly cleaned sodium pieces (0.043 g; 1.86 matom) in dry MeOH (30 ml) was added (S)-2-({3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carbothioyl}-amino)3-methyl-butyric acid methyl ester (0.9 g; 1.86 mmol) under stirring followed by iodomethane (0.23 ml; 3.72 mmol). The stirring was continued for 2 hours at room temperature. Hydroxylamine hydrochloride (0.284 g; 4.09 mmol) was added to this solution followed by NaHCO3 (0.343 g; 4.09 mmol) and the resulting reaction mixture was refluxed for 3 hours. The solid thus obtained was filtered, dried and purified by flash chromatography over silica gel with 5% MeOH in chloroform to obtain 0.61 g (68%) of the title compound. Mass (ES−): 482 (M−1); IR (KBr): 3384, 3196, 2963, 1737, 1642, 1611, 1546 (br), 1462 (br); 1H NMR (DMSO-d6) δ: 0.89, 0.94 (2×d, 6H), 2.08 (m, 1H), 3.65 (s, 3H), 3.99 (m, 1H), 5.85 (d, 1H), 7.20 (m, 1H), 7.29 (s, 1H), 7.66 (m, 1H), 7.79 (m, 1H), 7.93 (s, 4H), 10.78 (s, 1H); 10.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[N:22]=[C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[C:20]=1[CH3:37].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=3)[N:22]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C:20]=2[CH3:37])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3,3-dimethyl-6-morpholinoindoline (110 mg, 473 μmol), 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (137 mg, 473 μmol) in DMF (2 mL), and sodium hydride (38 mg, 946 μmol) and heating at 130° C. for 7 h. After purification 4-(1-(7-fluorophenyl)-3-methylquinolin-4-yl)-3,3-dimethylindolin-4-yl)-3,3-dimethylindolin-6-yl)morpholine was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94-8.03 (1H, m), 7.85 (1H, dd, J=10.0, 2.5 Hz), 7.52-7.68 (3H, m), 7.34-7.45 (2H, m) 7.14 (1H, d, J=7.8 Hz), 6.50 (1H, br s), 5.80 (1H, br s), 3.88 (1H, d, J=9.4 Hz), 3.57-3.79 (5H, m), 2.99 (4H, br s), 2.052 (3H, s), 1.46 (3H, s), 1.38 (3H, s). Mass Spectrum (ESI) m/e=486 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:11]>CCO.O.O=[Pt]=O>[ClH:11].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccnc1C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CCCNC1C(=O)O
Temperature: 25 °C

Procedure:
3-Methylpicolinic acid (50 g, 365 mmol) was dissolved in 400 mL of EtOH:H2O (1:1) with 60 mL of aq. HCl (32%). PtO2 (5 g) was then added and the reaction stirred at rt under a hydrogen balloon until NMR indicated completion. The reaction was filtered through diatomaceous earth and concentrated to yield the title compound as a white solid which was used without further purification (60.5 g, 92%). 1H NMR (MeOD, 400 MHz) δ 4.13-4.11 (m, 1H), 3.40-3.33 (m, 1H), 3.05-2.99 (m, 1H), 2.61-2.58 (m, 1H), 1.92-1.72 (m, 4H), 1.09 (d, J=7.0 Hz, 3H). MS (ESI) 452.16 (M+H).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[C:18]([C:22]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[C:2]2[C:3]=1[N:4]1[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]1)=[N:1]2)([CH3:21])([CH3:19])[CH3:17]
Reactant: Nc1ccccc1-c1cn2ccccc2n1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1nc2ccccc2c2nc3ccccn3c12

Procedure:
Preparation analogous to S. Sharma et al., J. Comb. Chem. 2007, 9, 783. A mixture of 20.9 g (100 mmol) of 2-imidazo[1,2-a]pyridin-2-ylphenylamine [127219-06-1], 42.1 g (500 mmol) of 2,2-dimethylpropanal [630-19-3] and 1.9 g (10 mmol) of p-toluenesulfonic acid hydrate in 500 ml of xylene is heated under reflux for 16 h, during which the water formed is removed by azeotropic distillation and a gentle stream of air is passed into the solution. After cooling, the solvent is removed in vacuo, the residue is taken up in 1000 ml of ethyl acetate, washed twice with 500 ml of water each time, once with 500 ml of saturated sodium chloride solution and dried over magnesium sulfate. After recrystallisation from ethanol twice, the solid is freed from low-boiling and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180° C.). Yield: 9.1 g (33 mmol), 33%, purity: about 99.5% (NMR).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].Cl[CH2:22][O:23][CH3:24]>CN(C=O)C>[CH3:22][O:23][CH2:24][O:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCOC[C@@H](CC(C)C)NC(=O)c1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of (R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (Example 71a) (0.24 mmol) dissolved in dry DMF (2 mL) was added at 0° C. powdered NaOH (0.36 mmol, 14.5 mg, 1.5 eq) and the mixture was stirred for 1 hr at 0° C. Then chloro-methoxy-methane (19.3 μl, 1 eq) was added and the reaction stirred at 0° C. for 1 hour. The reaction was quenched with water (30 mL) and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative TLC (20% ethyl acetate/hexanes) to give 37.7 mg of (R)—N-(1-(methoxymethoxy)-4-methylpentan-2-yl)-3,4-dimethylbenzamide (53%). 1H NMR (500 MHz, CDCl3): δ 0.98-1.00 (t, 6H), 1.49-1.53 (m, 1H), 1.58-1.64 (m, 1H), 1.69-1.73 (m, 2H), 2.32-2.33 (d, 6H), 3.38-3.39 (t, 3H), 3.64-3.72 (ddd, 2H), 4.41-4.44 (m, 1H), 4.65-4.69 (dd, 2H), 6.37-6.39 (d, 1H), 7.19-7.21 (d, 1H), 7.50-7.52 (dd, 1H), 7.60 (sb, 1H). MS (M+H, 294.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCOC(C)=O.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>[CH2:27]([O:29][C:30](=[O:49])[CH2:31][C:32]1[CH:33]=[C:34]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)[C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH3:28]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
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+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1
Temperature: 100 °C

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.100 g, 0.23 mmol) in DME (5 mL) was added [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.074 g, 0.23 mmol), followed by potassium carbonate (0.079 g, 0.58 mmol) and water (3 mL). The solution was purged with N2 for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.02 mmol) was added. The reaction was stirred at 100° C. until no starting material was seen by analytical LCMS and thin layer chromatography (tlc), and then cooled to room temperature and diluted with EtOAc. The mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography to give (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:2].[CH:22]1([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:44])=[C:32](OS(C(F)(F)F)(=O)=O)[C:33]=3[F:35])[C:28](=[O:45])[C:27]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:26]2)[CH2:24][CH2:23]1.O>C(N(CC)CC)C.CN(C)C=O>[CH:22]1([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:44])=[C:32]([C:2]#[C:1][C:3]4[CH:4]=[C:5]([CH2:6][C:7]5[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=5)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=4[O:18][CH3:19])[C:33]=3[F:35])[C:28](=[O:45])[C:27]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:26]2)[CH2:23][CH2:24]1
Reactant: C#Cc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(OS(=O)(=O)C(F)(F)F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 200 mg of 5-[3-ethynyl-4,5-dimethoxy-benzyl]-pyrimidine-2,4-diamine (Example 11b)), 207 mg of ethyl 1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-7-[[(trifluoromethyl)sulphonyl]oxy]-quinoline-3-carboxylate (J. Heterocyclic Chem., 28, 1581 (1991)) and 10 mg of bis-triphenylphosphinepalladium dichloride in 1.5 ml of triethylamine and 7.5 ml of dimethylformamide is stirred at 900 for one hr. The reaction mixture is cooled to room temperature, poured into 50 ml of water and extracted four times with 50 ml of methylene chloride each time. The combined organic phases are washed with 100 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with methylene chloride/methanol 9:1. 108 mg (39%) of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are isolated as a colourless solid. M.p.>230°. Mass spectrum: peaks: inter alia at 575 (M+, 36%), 503 (18%), 481 (20%), 123 (42%), 32(100%).