Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C@:11]([N:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])[CH3:18])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:19]([N:17]([CH3:18])[C@@:11]([CH3:16])([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:9][OH:8])=[O:33])=[O:20])=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CNC(=O)[C@@](C)(C(=O)NOCc1ccccc1)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@](C)(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 25.1 %

Procedure:
10% Pd—C (7.0 mg) was added to a methanol (2.6 mL) solution of (2S)-N-(benzyloxy)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N′,2-dimethylpropanediamide (21 mg) as obtained in Example 13-(1), and the mixture was stirred in a hydrogen atmosphere for 6 hours at room temperature. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=6/1) to obtain (2S)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′,2-dimethylpropanediamide (Compound 341, white solid) (4.2 mg, 27%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N[C@@](C)([C@H](O)C)CO.[CH:13]([C:16]([N+:21]([O-])=O)([CH2:19]O)[CH2:17][OH:18])([CH3:15])[CH3:14]>>[C:1]([O:4][CH2:19][C:16]([NH2:21])([CH:13]([CH3:15])[CH3:14])[CH2:17][OH:18])(=[O:3])[CH3:2]
Reactant: CC(C)C(CO)(CO)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: C[C@@H](O)[C@](C)(N)CO
Product: CC(=O)OCC(N)(CO)C(C)C
Yield: 98 %

Procedure:
Using the procedure in 30E, 2-isopropyl-2-nitro-1,3-propanediol (52A) gave a 98% yield of 2-amino-2-isopropyl-1,3propanediol acetate.1/4H2O mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32](Cl)[C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=1)[CH3:21]>CN(C)C=O.O>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]([CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH:32]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=1)[CH3:21]
Reactant: Cc1ccc(S)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(C)cc1
Temperature: 25 °C

Procedure:
ρ-Thiocresol (0.43 g) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.14 g) in dry N, N-dimethylformamide (23 mL,) under N2. The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate (1.31 g) in dry N,N-dimethylformamide (16 mL) and the mixture was then left stirring at room temperature for a further 12 hrs. The reaction mixture was diluted with water (375 mL) before extracting with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with water (3×100 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using 60% hexane in ethyl acetate as eluent to afford the title compound which solidified on standing, mp 88.6°-90.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:13])=O>>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH3:10])[C:5]([CH3:9])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Br)c[n+]([O-])c1C
Product: Cc1ncc(Br)c(Cl)c1C

Procedure:
5-bromo-2,3-lutidine-N-oxide (30.31 g) was added in portions to phosphorus oxychloride (41.3 ml) at 30°-40°. The mixture was heated to 50°, when an exothermic reaction raised the temperature to reflux. After 30 minutes the solution was cooled and poured onto ice to give a white solid, which was filtered off and discarded. The filtrate was extracted with ether then treated with 40% aqueous sodium hydroxide to pH 7, and extracted again with ether. The latter extract was dried (MgSO4) and stripped to give 5-bromo-4-chloro-2,3-lutidine, 12.0 g as a low melting solid.
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.C(O)(=[O:15])C.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8]([OH:15])=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(C2CC2(Cl)Cl)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C2CC2(Cl)Cl)cc1
Reaction time: 0.17 h

Procedure:
A solution of 50 g. (0.248 mole) of p-(2,2-dichlorocyclopropyl)aniline in 185 ml. of glacial acetic acid was cooled to about 10°C., and a solution of 18.9 g. (0.273 mole) of sodium nitrite in 185 ml. of water was added dropwise to the stirred solution. A thick slurry formed and this was added portionwise to a stirred solution of 160 ml. of concentrated sulfuric acid in 320 ml. of water held at 100°-105°C. The reaction mixture was stirred at 100 ± 5°C. for 10 minutes, then cooled and diluted with water. The resulting product was collected by filtration, dissolved in ether and washed with sodium bicarbonate solution. The ether solution was then extracted with sodium hydroxide solution, and the sodium hydroxide solution was acidified and extracted with ether. The ether solution was dried and concentrated in vacuo, and the residue (18 g.) was steam distilled affording 9 g. of a yellow gum which crystallized when triturated with ether. There was thus obtained 8 g. of p-(2,2-dichlorocyclopropyl)phenol, m.p. 54.5°-56°C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:39][OH:40])[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:25]([F:38])[CH:24]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:40][N:39]=[C:22]([C:23]3[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:25]([F:38])[CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reactant: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Product: CCOC(=O)CCCOc1ccc(-c2noc(-c3ccc(-c4ccccc4CC)c(COC)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 36 (202.74 mg; 0.75 mmol) and Intermediate 66 (234.54 mg; 0.83 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.41 (d, J=1.3 Hz, 1H), 8.15 (dd, J=7.9, 1.8 Hz, 1H), 7.95-7.90 (m, 2H), 7.41-7.34 (m, 3H), 7.29-7.23 (m, 1H), 7.12-7.05 (m, 2H), 4.22-4.13 (m, 6H), 3.33 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.50-2.28 (m, 2H), 2.24-2.17 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H). LC/MS (Method B): 519.4 (M+H)+. HPLC (Method A) Rt 6.62 min (Purity: 99.9%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:12][OH:13])[CH3:11])=[N:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:27][O:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:12][O:13][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[CH:27][O:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])[CH3:11])=[N:2]1
Reactant: CC(=NO)c1noc2ccccc12
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC=C(C(=O)OC)c1ccccc1CON=C(C)c1noc2ccccc12

Procedure:
A mixture of 0.8 g of 1-(1,2-benzisoxazol-3-yl)ethanone oxime, 1.3 g of methyl 2-(bromomethyl)-α-(methoxymethylene)phenylacetate and 1 g of potassium carbonate in 15 ml of acetonitrile is refluxed for 4 h. The reaction mixture is cooled and filtered and the filtrate is concentrated under vacuum. The residue is dissolved in ethyl acetate and the solution is washed twice with water and once with a saturated solution of sodium chloride and dried over sodium sulfate. After removal of the solvent under vacuum, the residue is purified by chromatography on silica gel with ethyl acetate/hexane (1:3), giving the title compound having a melting point of 97°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1>>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([C:15]#[C:14][C@:9]2([O:23][C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:27]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])[CH:17]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (3-trifluoromethyl-phenyl)-acetic acid to yield (3aR,4S,7aR)-methyl 4-(m-tolylethynyl)-4-(2-(3-(trifluoromethyl)phenyl)acetoxy)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=8.365 min; LCMS Method III
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH3:31].[CH2:32]([N:34](CC)CC)[CH3:33].ClCC#N>CO>[C:32]([CH2:33][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[C:25]5[CH3:31])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1)#[N:34]
Reactant: CCN(CC)CC
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Agent: N#CCCl
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A mixture of 6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (460 mg, 1.10 mmol), (prepared as described in Example 276), triethylamine (5 ml) and chloroacetonitrile (0.38 ml, 6.05 mmol) in methanol (5 ml) was stirred at ambient temperature for 24 hours. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product recrystallised from acetonitrile to give 7-(1-cyanomethylpiperidin-4-ylmethoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (178 mg, 35%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].CN(C)C(Cl)=O.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>>[CH3:26][N:27]([CH3:31])[C:28](=[S:29])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: CN(C)C(=S)Cl
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Agent: CN(C)C(=O)Cl
Product: CCCC12COC(c3ccc(C#CC(=S)N(C)C)cc3)(OC1)OC2

Procedure:
N,N-Dimethyl-3-[4-(4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynamide and N,N-dimethyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]-oct-1-yl) phenyl]-prop-2-ynthioamide were prepared using similar methodology from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and dimethylcarbamoyl chloride and dimethylthiocarbamoyl chloride respectively.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]3[O:24][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(=NO)c1ccncc1
Product: CCc1ccc(C2CC(c3nc(-c4ccncc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 39 mg (45% of theory)
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(=O)OCC>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (1226 mg, 3.43 mmol) in THF (15 mL) was added n-BuLi (2.145 mL, 3.43 mmol), stirred for 10 min. then 3-fluoro-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (0.691 mL, 3.12 mmol) was added. The mixture was stirred at 0° C. for 1 h, then at room temperature for another 2 h. The reaction mixture was diluted with EA, washed with water, brine (50 mL), and concentrated. The residue was purified via flash chromatography to afford the title compound (449 mg, 49.8% yield) as colorless oil. LCMS: rt=3.13 min
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>[Pd](Cl)Cl.C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C[SiH](Cl)Cl
Agent: Cl[Pd]Cl
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCCCCCC
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 290 %

Procedure:
As described in Example 2, 2.87 g (0.0217 mol) of dicyclopentadiene, 3.74 g (0.0326 mol) of methyldichlorosilane, 0.036 g (0.000203 mol) of palladium dichloride, 100 μL (0.000406 mol) of tributylphosphine, 4 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 180° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (11.4 g) of (2-cyclopentenyl)methyldichlorosilane (4.3 g, 72%), other unreacted reactants, toluene, hexadecane, and unidentified compounds.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:32])=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:17]([O:30][CH3:31])[CH:16]=3)[CH:14]=2)[CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[CH3:31][O:30][C:17]1[CH:16]=[C:15]([C:13]2[CH:14]=[C:9]([C:4]3[CH:3]=[C:2]([C:37]4[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=4)[N:7]=[CH:6][C:5]=3[NH2:8])[C:10]([F:32])=[N:11][CH:12]=2)[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(-c2cnc(F)c(-c3cc(Cl)ncc3N)c2)cc(OC)c1CN1CCCCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc(F)c(-c3cc(-c4cnn(C)c4)ncc3N)c2)cc(OC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A degassed mixture of 6′-chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (830 mg, 1.40 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (577 mg, 2.78 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (151 mg, 0.19 mmol) in 1N aqueous potassium fluoride solution (10 mL) and acetonitrile (6 mL) was heated under microwave irradiation at 100° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (494 mg, 54%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.55 (dd, J=2.5, 1.0 Hz, 1H), 8.22 (dd, J=8.8, 2.5 Hz, 1H), 8.16 (d, J=0.6 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 6.95 (s, 2H), 4.35 (s, 2H), 4.01 (s, 6H), 3.95 (s, 3H), 3.61-3.22 (br m, 2H), 3.19-2.90 (br m, 2H), 2.02-1.47 (br m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.Br[CH2:42][CH2:43][CH2:44][OH:45]>>[OH:45][CH2:44][CH2:43][CH2:42][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: OCCCBr
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCO)cc3)cc21

Procedure:
Analogously to Method I, 0.200 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.045 ml of 3-bromopropanol is used to obtain the title compound as a colourless oil. Rf=0.19 (1:3 EtOAc-heptane); Rt=4.90.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)=[O:26])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:36][C:37]1[C:42]([C:43]#[N:44])=[C:41](Cl)[N:40]=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:36][C:37]1[C:42]([C:43]#[N:44])=[C:41]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]4)=[O:26])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:40]=[CH:39][N:38]=1
Reactant: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)CC1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a solution of (S)-2-(1-aminoethyl)-5-(6-(4-isopropylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, purity 10%, 0.03 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (6 mg, 0.04 mmol) in tert-butanol (3 ml) was added DIEA (44 μl, 0.25 mmol) and the reaction mixture was stirred at 120° C. for 2 days. The solvent was removed under reduced pressure. Ethyl acetate was added and the organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 4 mg (25% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>>[CH3:22][N:23]([CH3:25])/[CH:24]=[C:12]1\[C:11](=[O:16])[CH:10]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:15][CH2:14][CH2:13]\1
Reactant: O=C1CCCCC1c1cc(F)c(F)c(F)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C1/CCCC(c2cc(F)c(F)c(F)c2)C1=O

Procedure:
2-(3,4,5-Trifluoro-phenyl)-cyclohexanone (100 mg, 0.44 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (123 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 284.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].I[CH3:19].[H-].[Na+].O>C1COCC1>[CH3:19][N:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1]
Reactant: CI
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)n(C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
To ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3 g, 13 mmol) in THF (50 ml) was added iodomethane (4 ml, 65 mmol) and sodium hydride (630 mg, 60% in mineral oil, 15.6 mmol) at 0° C. After warming the reaction mixture to room temperature, it was stirred for 1 day. Water (20 ml) was added and extracted organic layer with diethyl ether. With normal-phase preparative LC, purification preceded to gave title compound (3 g, 94%) as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Subsequently, to a solution of (2-hydroxyethyl)carbamic acid benzyl ester (5.37 g, 27.5 mmol) in dimethylformamide (160 ml) were added t-butyldiphenylsilyl chloride (8.6 ml, 33.0 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol was added thereto and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:1) as the eluant to afford [2-(t-butyldiphenylsilyloxy)ethyl]carbamic acid benzyl ester (11.93 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=[C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=4)[NH:10][C:9]3=[O:14])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
5-Aminosulfonyl-2-oxindole was condensed with indole-5-carbaldehyde to give the title compound.