Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][CH:18]([CH3:21])[CH2:19][NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][O:17][CH:18]([CH3:21])[CH2:19][NH:20][CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(CN)OCc1ccccc1
Reactant: c1ccc(C2CO2)cc1
Product: CC(CNCC(O)c1ccccc1)OCc1ccccc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
A mixture of styrene oxide (1.96 g, 0.010 mol) and 2-benzyloxypropylamine (2.48 g, 0.15 mol) was heated at 140° C. for 6 hours and then allowed to cool to ambient temperature and stand for 12 hours. The solidified reaction mixture was triturated with isooctane and filtered to obtain an impure solid that was recrystallized from isooctane to obtain 2.40 g of a white solid (84% yield); mp 90°-100° C. (undefined).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:30]([O:34][C:35]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH:39]2[O:45][CH:43]([CH2:42][N:41]([CH2:16][CH2:15][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][CH:28]=3)[C:11]([NH:13][CH3:14])=[O:12])[CH2:40]2)[CH2:44]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CNC(=O)N(CCOc1ccc(C#N)cc1)CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Temperature: 45 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-3-methylureido}ethyl ester (1.35 g, 3.233 mmol; see Preparation I above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (1.48 g, 6.466 mmol; see WO 01/28992) and potassium carbonate (1.34 g, 9.7 mmol) in dry acetonitrile (15 mL) was stirred at 45° C. for 24 h. The reaction mixture was diluted with 20 mL water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel (using 2-2.5% methanol in dichloromethane) and further purification by preparative HPLC yielded 920 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1ccc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccc(C)nc3)nc12

Procedure:
From (6-methyl-pyridin-3-yl)-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>ClCCl>[Cl:30][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN(CCCCC(=O)O)C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CN(CCCCC(=O)Cl)C(=O)OCc2ccccc2)cc1

Procedure:
5.6 g (15 mmol) of the 5-{[(benzyloxy)carbonyl](4-methoxybenzyl)amino}valeric acid are dissolved in 60 ml of dichloromethane, and 2.2 ml of thionyl chloride are added. The mixture is heated under reflux for 30 min. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 5.7 g (98% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:19]=[O:20]
Reactant: O=N[O-]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
To a stirring mixture of 6-amino-1-pentylpyrimidine-2,4(1H,3H)-dione (4.0 g, 0.020 mol) and acetic acid (20 mL, 0.4 mol) in water (20 mL) was slowly added sodium nitrite (1.5 g, 0.022 mol). Stirring was continued at room temperature for 2 h at which time the reaction mixture became pink and precipitate formed. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in aqueous NaOH solution and extracted with methylene chloride to remove byproducts. The aqueous solution was neutralized with HCl and concentrated. The residue was treated with methanol and filtered. The filtrate was concentrated to give the desired product as pink solid. LCMS calculated for C9H15N4O3 (M+H): 227.1. found: 227.1 (M+H), 249.1 (M+Na).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]5[CH2:25][CH2:24][O:23][CH2:22]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(CO[C@H]4CCOC4)n3)c2n1
Reactant: OB(O)c1ccccc1
Product: Nc1nc(-c2ccccc2)c2nnn(Cc3cccc(COC4CCOC4)n3)c2n1

Procedure:
This was prepared from 7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and phenylboronic acid by the method of Example 13 to give 0.060 g (68%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([C:22]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@H:11]3[CH2:12][CH2:13][O:14][CH2:15]4)(=O)C.[OH-].[K+].P(=O)(O)(O)O>CC(O)C.O>[C:22]([N:21]1[CH2:20][CH2:19][C@@:16]23[C:17]4[CH:18]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=4[CH2:9][C@@H:10]1[C@@H:11]2[CH2:12][CH2:13][O:14][CH2:15]3)([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: CC(=O)Oc1ccc2c(c1)[C@]13CCN(C(=O)Oc4ccccc4)[C@H](C2)[C@@H]1CCOC3
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(Oc1ccccc1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A cooled solution of XXVII from Step (b) above (0.01 m) in 25 ml 2-propanol (~10° C.) is treated with a solution of potassium hydroxide (3 g) in 25 ml water and is stirred under nitrogen at 10° C. for 2 hours. The reaction mixture is acidified with phosphoric acid and the 2-propanol removed at reduced pressure. The aqueous mixture is extracted with methylene chloride. The extracts are dried (MgSO4) and concentrated to produce the title compound.
Reaction SMILES: FC(F)(F)C(O[C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+]>COCCOC.CO.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>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OC(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of Example 6A (4.0 g, 12 mmol) and 4-fluorophenylboronic acid (1.68 g, 12 mmol) in 1,2-dimethoxyethane (100 mL) and methanol (50 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.416 g, 0.36 mmol) and CsF (3.64 g, 24 mmol), heated to reflux, and stirred overnight. The reaction was concentrated and the concentrate was dissolved in ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:6 ethyl acetate/hexanes to provide the desired product (2.6 g, 78%). MS (CI) m/e 278 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][C:17]([Cl:23])=[O:19])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCc1c(Cl)cccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCc1c(Cl)cccc1-c1ccccc1
Reaction time: 18 h

Procedure:
Under a dry argon atmosphere a stirred solution of 4-(3-chloro[1,1'-biphenyl]-2-yl)butanoic acid (22.8 g, 0.083 mole) in toluene (500 ml) was heated at 65°. Oxalyl chloride (21 g, 0.166 mole) was added slowly to the reaction mixture. After complete addition the mixture was allowed to stir at 40° for approximately 18 hours. The solvent and excess oxalyl chloride were removed by distillation under reduced pressure. Further distillation under reduced pressure gave 4-(3-chloro[1,1'-biphenyl]-2-yl)butanoic acid chloride (b.p. 150°/0.04 mm) as a clear oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]1([C:11]2[C:12](=[O:17])[O:13][CH2:14][CH2:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[Si](C)(C)C>O1CCCC1.[Cu]I>[C:5]1([CH:11]2[CH:16]([CH:1]=[CH2:2])[CH2:15][CH2:14][O:13][C:12]2=[O:17])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1OCCC=C1c1ccccc1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C=CC1CCOC(=O)C1c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Vinylmagnesium bromide (77 ml, 1M THF) was added to a slurry of copper (I) iodide (7.37 g) in tetrahydrofuran (80 ml) at −78° C. under a nitrogen atmosphere. This mixture was stirred at −40° C. for 30 minutes, then recooled to −78° C. A solution of 3-phenyl-5,6-dihydro-2-pyrone (J. Org. Chem. 1967, 32, 2354) (4.6 g) and chlorotrimethylsilane (3.28 ml) in THF (80 ml) was added to the stirred mixture. Thin layer chromatography showed all starting material had reacted. The mixture was quenched with ammonium chloride (saturated aqueous solution) at −78° C. and the resulting mixture was allowed to come to room temperature and was stirred for 2 hours until the aqueous layer became dark blue. The mixture was filtered through Celite™ to remove any insoluble inorganics and the solution was extracted with ethyl acetate (3×100 ml). The pooled organic extracts were washed with brine, dried (MgSO4) and concentrated to give a yellow oil. This was purified on silica using 30-40% ether in hexane as eluant to afford the title compound (4.9 g, crystallised on standing) as a mixture of cis and trans isomers (2:1). Recrystallisation of this mixture from ether-hexane afforded the pure cis isomer as white prisms.
Reaction SMILES: [Cl:1][C:2]1[C:10](F)=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[Na].[CH3:19][O:20][CH2:21][CH2:22][SH:23]>CN(C=O)C.O>[Cl:1][C:2]1[C:10]([S:23][CH2:22][CH2:21][O:20][CH3:19])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Reactant: COCCS
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COCCSc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.0 g (19.8 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid (synthesis described in WO 98/42648) were taken up in 40 ml of DMF. 871 mg (21.8 mmol, purity 60% by weight) of NaH were added. The mixture was stirred at RT for 30 minutes. A reaction mixture containing the sodium salt of 2-methoxyethanethiol (prepared from a solution of 2.19 g (23.7 mmol) of 2-methoxyethanethiol in 10 ml of DMF which had been added dropwise to a suspension of 950 mg (23.7 mmol, purity 60% by weight) of NaH in 30 ml of DMF, followed by stirring at RT for 30 minutes) was then added a little at a time. During the addition, the temperature was kept below 30° C. The reaction mixture was stirred at RT for 16 h, for work-up diluted with water and washed with diethyl ether. The aqueous phase was acidified with 1M HCl and extracted with tert-butyl methyl ether. The organic phase was dried and filtered. The aqueous phase was additionally extracted with EA, and the organic phase was also dried and filtered. The filtrates of the organic phases were combined and freed from the solvent. The residue was dried under reduced pressure and purified chromatographically. This gave 4.8 g of the pure product.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][C@@H:16]([CH2:23][S:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C>>[ClH:1].[CH3:25][S:24][CH2:23][C@H:16]([NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CSC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution (35 ml) of 4-N HCl/dioxane was added to 2.65 (10.0 mmols) of N-tert-butoxycarbonyl-(R)-α-methylthiomethylbenzylamine, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was concentrated with the addition of 30 ml of ether to obtain (R)-α-methylthiomethylbenzylamine hydrochloride in a quantitative yield.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>O1CCOCC1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:33])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(Br)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2Br)c1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
The compound of example 1 (60 mg, 0.118 mmol) was dissolved in dioxane (1.5 ml), lithium hydroxide (0.59 ml of an aqueous 1 M solution) was added and the mixture was reacted for 20 min at 60° C. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the organic extracts were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was stirred overnight with a mixture of diethyl ether and HEP, filtered, and the solid was dried in vacuo to give 43 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:11][CH:12]([CH3:15])[CH2:13]I.O>C1COCC1>[CH2:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:12]([CH3:15])[CH3:13]
Reactant: c1ccsc1
Reactant: CC(C)CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1cccs1
Temperature: -40 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
A solution of thiophene (6.00 g, 0.0714 mol) in 80 mL of THF (80 mL) was treated with n-BuLi (1.6 M in hexane, 54 mL, 0.0864 mol) at −78° C. The mixture was stirred at −40° C. for about 2 hours. The solution was then cooled to −78° C. again and treated with 2-methylpropyliodide (16.04 g, 0.0871 mol). The solution was stirred at 0° C. for 2 hours, and then overnight at room temperature for about 16 hours. The solution was treated with water (25 mL) and extracted with petroleum ether (3×25 mL). The organic layer was dried over magnesium sulfate and filtered. The crude product was purified by distillation (54-55° C. at 12 mmHg) to give the sub-title compound (3.0 g, 0.0213 mol) in 30% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:30](=[O:31])[CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:33])([F:34])[F:17])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described in example 8 c], (6-amino-indol-1-yl)-acetic acid ethyl ester (WO 2003041714 A1) was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid in the presence of 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride and 4-(dimethylamino)pyridine to give the title compound as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)Nc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.00 g, 7.29 mmol) in DMA (18 ml) at room temperature was added tert-butylamine (2.4 ml, 22.03 mmol) and DIPEA (4.0 ml, 22.90 mmol). The reaction mixture was heated to 50° C. and stirred for one day. The temperature was increased to 70° C. and the reaction mixture was stirred for two days. The temperature was further increased to 120° C. and the reaction mixture was stirred for 8 h. The reaction mixture was then transferred into a sealed vial, additional tert-butylamine (1 mL, 9.18 mmol) was added and the mixture was continued to stir at 120° C. for another 4 days. The crude mixture was concentrated and purified by column chromatography on silica gel using a gradient of MeOH (0-3%) in DCM to yield the title compound as a white solid mixed with a brown liquid. The material was dissolved in DCM and aqueous citric acid (<10%). Layers were separated, the aqueous layer was washed with DCM.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:39])(=[O:38])[C@H:31]([C@@H:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32]>C(O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:39])(=[O:38])[C@H:31]([C@@H:33]([C:35]([O-:37])=[O:36])[OH:34])[OH:32]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCO
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (7.42 g, 18.6 mmol) was dissolved in boiling ethanol (700 ml), to which a solution of D-tartaric acid (1.40 g) in ethanol (20 ml) was added and left to cool to room temperature to give 8.08 g of sunitinib D-tartarate: Melting point: 233-235° C. (Form IV), ratio sunitinib/tartaric acid (according to NMR) 2:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:15](=[NH:16])[C:14]([Cl:18])([Cl:17])[Cl:13])=[CH:5][CH:4]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Add a solution of 4-methoxybenzyl alcohol (31 mL, 250 mmol) in diethyl ether (250 ml) to sodium hydride (1.0 g, 25 mmol, 60% suspension in mineral oil) in diethyl ether (250 ml). Stir 30 min. Cool in ice bath and add trichloroacetonitrile (25 mL, 250 mmol) and let slowly warm to room temperature. Concentrate and dissolve in petroleum ether containing 0.3% methanol (330 mL) and filter through a filtering agent and concentrate to give the title compound (67 g, 95%).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[C:24]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(COc1ccc(CC(Cl)C(N)=O)cc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)NC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1
Yield: 88.8 %

Procedure:
In 3 ml of toluene is dissolved 2.8 g of 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionamide, and to the solution are added 1.0 g of acetic anhydride and one drop of concentrated sulfuric acid. The mixed solution is stirred under heating at 100° to 110° C for 1.5 hour. After cooling, the solvent is distilled off and water is added to the residue. The resulting crystals are recrystallized from ethanol to give 2.8 g of N-acetyl-2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionamide.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH2:6][C:5]=12.[CH2:24](Br)[CH:25]=[CH2:26]>>[CH2:26]([C:9]1([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=2)[N:4]2[CH:3]=[N:2][CH:1]=[C:5]2[CH2:6][CH2:7][CH2:8]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(-c2ccccc2)c1
Product: C=CCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21

Procedure:
6-(5-Allyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrile is prepared from 6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrile and allyl bromide by analogy to 19A above. MS (ESI) m/z 340 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm (HCl salt) 1.73-1.98 (m, 2H), 2.02-2.16 (m, 1H), 2.23-2.38 (m, 1H), 2.54-2.65 (m, 1H), 2.68-2.83 (m, 1H), 2.86-3.02 (m, 1H), 3.00-3.14 (m, 1H), 5.11 (d, J=17.2 Hz, 1H), 5.23 (d, J=10.1 Hz, 1H), 5.44-5.69 (m, 1H), 6.87 (d, J=7.3 Hz, 1H), 6.92 (s, 1H), 7.02-7.12 (m, 1H), 7.13-7.22 (m, 1H), 7.27-7.39 (m, 3H), 7.45 (d, J=2.0 Hz, 1H), 7.71 (dd, J=8.5, 1.9 Hz, 1H), 8.31 (s, 1H).