Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:8][C:9]1[CH:10]=[C:11]([C:15]([OH:44])([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:16]([N:18]2[CH2:37][CH2:36][CH2:35][C@H:19]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[O:21])=[O:17])[CH:12]=[CH:13][CH:14]=1.C(=O)(O)[O-:46].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.CCOC(C)=O>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:8][C:9]1[CH:10]=[C:11]([C:15]([OH:44])([C:38]2[CH:39]=[N+:40]([O-:46])[CH:41]=[CH:42][CH:43]=2)[C:16]([N:18]2[CH2:37][CH2:36][CH2:35][C@H:19]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[O:21])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCc1ccccc1-n1cnnn1)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1-n1cnnn1)[C@@H]1CCCN1C(=O)C(O)(c1cccc(Cl)c1)c1ccc[n+]([O-])c1
Reaction time: 2 h

Procedure:
The TFA salt of the polar isomer of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-N-[2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (0.01 g, 0.02 mmol) was partitioned between EtOAc and saturated sodium bicarbonate solution and extracted with EtOAc to retrieve the free base. To a stirred solution of the dried free base of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-N-[2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (0.009 g, 0.017 mmol) in dichloromethane (1 mL), cooled to 0° C., was added 3-chloroperoxybenzoic acid 70% (0.006 g, 0.026 mmol). After 2 hours, the reaction was evaporated in vacuo and purified on a Gilson Preparative HPLC. Pure fractions were combined, freeze dried and lyophilized to yield the solid TFA salt of 1-[(3-chlorophenyl)(hydroxy)(1-oxidopyridin-3-yl)acetyl]-N-[2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (0.003 g, HPLC RT=2.70 min, Method A; LCMS m/z=534).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:19])=[N:14]2)[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CCO>[C:10]([C:8]1[CH:7]=[C:6]([N:13]2[C:17](=[O:18])[C:16](=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=3)[C:15]([CH3:19])=[N:14]2)[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1)([OH:12])=[O:11]
Reactant: CC1=NN(c2cc(C(=O)O)cc(C(=O)O)c2)C(=O)C1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CC1=NN(c2cc(C(=O)O)cc(C(=O)O)c2)C(=O)C1=Cc1ccc(N(C)C)cc1

Procedure:
A slurry composed of 1-(3,5-dicarboxyphenyl)-3-methyl-2-pyrazoline-5-one (44.6 grams, 0.17 mol), 4-dimethylaminobenzaldehyde (26.9 grams, 0.18 mol) and EtOH (500 mL) was heated at reflux for three hours. The reaction mixture was chilled in ice and the resulting crude orange product was isolated by filtration and washed with EtOH (200 mL). The product was purified by three repetitive slurries of the solid in acetone (1.4 1) at reflux and filtering to recover the dye. The mp of the product was above 310° C. The NMR and IR spectra were consistent with the structure assigned. The C, H and N elemental analyses were in agreement with those calculated for the empirical formula for the dye.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.CN(C)C=O>[Cl:1][CH2:2][C:3]([O:11][Si:18]([CH3:21])([CH3:20])[CH3:17])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCl)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CCl)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cold solution of 7.22 g. of 4-chloromethyl-4-hydroxy-1-octyne and 7.16 g. of imidazole in 28 ml. of dimethylformamide is added 6.5 ml. of trimethylchlorosilane via a syringe during 15 minutes. The resulting mixture is stirred at room temperature overnight, diluted with hexane and poured into a mixture of ice and saturated sodium bicarbonate solution. The hexane solution is separated, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 11.8 g. of a colorless liquid which is vacuum distilled at b.p. 50°-57° C./3.5-4 mm. to give 9.7 g. of product as a colorless liquid; PMR δ 3.58 (s), 2.50 (d), 1.99 (t), 0.87 (s, OTMS).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-:23].[Na+].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N+:8]([O-:23])=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2ncc3ncn(-c4ccccc4Cl)c3c2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2ncn(-c3ccccc3Cl)c2c2cc(Cl)ccc21
Reaction time: 2 h

Procedure:
3.01 g (9.508 mmol) 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline (Example 25), 1.22 g (11.4 mmol) sodium carbonate and 2.6 g (10.45 mmol) 3-chloroperoxybenzoic acid in 75 ml chloroform are stirred at rt for 5 h. After this time, a further amount of 254 mg of sodium carbonate, 472 mg 3-chloroperoxybenzoic acid and 50 ml chloroform are added and stirring is continued for 2 h at 50° C. The cold solution is washed with sat. sodium bicarbonate solution (2×), 0.1 N sodium thiosulfate (2×) and brine (2×). The organic phase is dried over sodium sulfate and the solvent evaporated. Purification of the title compound is achieved by chromatography (CH2Cl2-methanol 95:5→90:10) and crystallization (ethyl acetate-hexane). mp: 247-250° C.; MS: 330 (M++1); HPLC: tret=11.25 min (Grad 1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxyacetophenone (101 g, 744 mmol) in acetone (1 L) were added potassium carbonate (154 g, 1.12 mol) and benzyl bromide (130 g, 759 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-4:1) to give the objective substance (128 g, 76%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:39]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:38]=4[N:29]=[CH:30][CH:31]=[CH:32]5)(=[O:40])=[O:41])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5cccnc45)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-d hydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and quinoline-8-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=O)C.Br[CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16]>>[CH:15]([O:14][CH2:13][CH2:12][O:10][CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)([CH3:17])[CH3:16]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: CC(C)OCCBr
Product: CC(C)OCCOC1CCNCC1

Procedure:
This compound was prepared similarly to Example A from N-acetyl-4-hydroxypiperidine and 1-bromo-2-isopropoxyethane. The compound was characterized by spectroscopic techniques.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16]C(C4C5C=CN(S(C6C=CC(C)=CC=6)(=O)=O)C=5C=CN=4)C)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of (±)—N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethyl)pyrimidine-2,4-diamine (563 mg, 1.10 mmol) and sodium hydroxide (132 mg, 3.29 mmol) in MeOH (20 mL) and water (50 mL) was stirred at 80° C. for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC to afford N2-1-(1H-pyrrolo[3,2-c]pyridin-4-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine: MS (ESI) m/z: 361.2 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH:9]=[CH:8]1)=[O:6].[O:16]1CCC[CH2:17]1>>[CH3:1][N:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[C:5](=[O:6])[N:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[C:17]1=[O:16]
Reactant: CNc1ccccc1C(=O)N1C=CCC1
Reactant: C1CCOC1
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 24.8 g. of racemic 1-(N-methylanthraniloyl)pyroline and 21 g. of dicyclohexylcarbonyl diimide in 300 ml. of tetrahydrofuran is stirred at room temperature for 24 hours and then heated on the steam bath for 4 hours. The reaction mixture is filtered to remove the insoluble dicyclohexyl urea and the mother liquid is concentrated to recover the desired product, which is further purified by recrystallization from ethyl acetate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[CH:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CCOCC.O1CCCC1.O>[CH:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29]3[O:18][N:17]=[C:15]([C:13]4[O:14][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=4)[N:16]=3)=[CH:27][CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)cc3)n2)o1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxyfuran-2-carboximidamide (0.19 g, 0.70 mmol) that was obtained in Example 2 (2b), 4-cyclohexylbenzoic acid (0.16 g, 0.77 mmol), and N,N′-dicyclohexylcarbodiimide (0.17 g, 0.84 mmol) in dichloromethane (1.5 ml) was stirred for 1 hour. After stirring, the reaction mixture was diluted with ether, and insoluble materials were removed by filtration with Celite, and then the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (1.0 ml) was added tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 1.1 ml, 1.1 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 1 hour. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.18 g) in a yield of 81% as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=1)[CH2:2][CH2:3][CH3:4].O[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C(=O)N(C)C>[CH2:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Oc1cccnc1
Reactant: CCCCOC(=O)c1ccc(F)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C(=O)N(C)C
Product: CCCCOC(=O)c1ccc(-c2cccnc2)c(C(C)=O)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
1.5 g of 3-acetyl-4-fluoro-benzoic acid n-butylester, 0.6 g of 3-hydroxypyridine and 4.1 g of Cs2CO3 are stirred in 20 ml of tetramethylurea for 2 h at 110° C. After cooling to RT the mixture is poured into 200 ml EE and the mixture is washed 3 times with 100 ml brine. Drying takes place over Na2SO4 and the solvent is distilled off in vacuo. Chromatography over silica gel with MTB furnishes 1.3 g of a pale yellow oil. Rf (MTB)=0.30 MS (DCI): 314 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:33]([O-])=O)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1.O1CCCC1>C(O)(=O)C.[Fe]>[NH2:33][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=2[CH:25]=1)=[O:12]
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3[N+](=O)[O-])C(F)(F)F)cc12
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3N)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.3 %

Procedure:
42 mg of 6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is dissolved in 1 ml of acetic acid and 1 ml of tetrahydrofuran b, mixed with 22.5 mg of iron powder and stirred for 16 hours at room temperature. It is suctioned off on diatomaceous earth, concentrated by evaporation, the residue is taken up in ethyl acetate and washed with a saturated sodium hydrogen carbon solution. After chromatography on silica gel with hexane/ethyl acetate (1.5+1) and recrystallization from diisopropyl ether, 10 mg of 6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained, flash point 208° C.
Reaction SMILES: [CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]>CCOC(C)=O>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=1
Reactant: COC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: COC(=O)CN(C)Cc1ccc(N)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of methyl 2-(methyl(4-nitrobenzyl)amino)acetate (0.800 g, 3.36 mmol) and Pt2O (0.080 g, 0.352 mmol) in EtOAc (30 ml) was hydrogenated at 15 psi for 1 hour. The catalyst was filtered off, and the solvent was removed. Methyl 2-((4-aminobenzyl)(methyl)amino)acetate was obtained (0.680 g, 3.27 mmol, 97% yield, MS/ESI+ 209.2 [MH]+) and used in the next step without further purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH2:8].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:32]1[N:31]=[C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([NH:22][CH2:21][CH2:20][C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[NH:13][CH:12]=[C:11]4[C:9]#[N:10])=[O:37])=[CH:29][CH:28]=2)[CH:35]=[CH:34][N:33]=1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NC1CC2CCC1C2
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NC5CC6CCC5C6)n4)cc3)cc12

Procedure:
Using Bicyclo[2.2.1]hept-2-ylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 477 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:17][C:18]([NH:20]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[S:19])[C@H:14]([CH2:15]O)[CH2:13][CH2:12][O:11][CH2:10]1.Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][CH2:12][CH2:13][C@H:14]1[CH2:15][S:19][C:18]([NH2:20])=[N:17]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CO
Product: NC1=N[C@@]2(c3ccc(F)cc3F)COCC[C@H]2CS1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of 9H-fluoren-9-ylmethyl {[(3S,4R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate (C12) (1.417 g, 2.701 mmol) in methanol (20 mL) was treated with concentrated hydrochloric acid (12 M, 0.675 mL, 8.10 mmol) and heated at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (20 mL) and treated with piperidine (2 mL); this reaction mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 7% methanol in dichloromethane) provided the product as a white solid. Yield: 281 mg, 0.988 mmol, 37%. LCMS m/z 285.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.45-1.52 (m, 1H), 1.99-2.12 (m, 1H), 2.67-2.73 (m, 1H), 2.82-2.90 (m, 2H), 3.62-3.70 (m, 1H), 3.63 (br d, J=10.9 Hz, 1H), 3.99-4.05 (m, 2H), 6.92-7.00 (m, 2H), 7.35 (ddd, J=9.5, 8.7, 6.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>>[CH:11]1([NH:10][C:6]2[C:7]([CH:8]=[O:9])=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=3[CH3:26])[N:3]=[C:4]([S:14][CH3:15])[N:5]=2)[CH2:13][CH2:12]1
Reactant: CSc1nc(Cl)c(C=O)c(NC2CC2)n1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CSc1nc(NC2CC2)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.69 (m, 2H), 0.94 (m, 2H), 2.23 (s, 3H), 2.62 (s, 3H), 3.14 (m, 1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.09(br s, 1H), 9.49 (s, 1H). LC MS (m/e)=318 (MH+).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([OH:17])[C:14]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10])[CH:4]=[CH2:5]>CO.O>[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([OH:17])[C:14]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(O)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc(O)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 2 ml) was added to a mixture of methyl 2-allyloxy-4-hydroxy-5-isopropylbenzoate (860 mg, 3.44 mmol) in methanol (12 ml) and water (4 ml) and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford 2-allyloxy-4-hydroxy-5-isopropylbenzoic acid (715 mg, 88%) as a pale green solid. 1H NMR (DMSO-d6) 11.92 (1H, br s), 10.08 (1H, s), 7.56 (1H, s), 6.48 (1H, s), 6.03 (1H, m), 5.50 (1H, dm), 5.27 (1H, dm), 4.53 (2H, m), 3.11 (1H, m), 1.13 (6H, d). MS: [M+Na]+ 259.
Reaction SMILES: [CH3:1][O:2][Na].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]>CO>[F:4][C:5]1[CH:6]=[C:7]([C:8](=[NH:9])[O:2][CH3:1])[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(F)c1
Reactant: CO[Na]
Solvent: CO
Product: COC(=N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 1000.1 %

Procedure:
MeONa (2.35 g, 41 mmol) was added to a stirred solution of 3-fluorobenzonitrile (50.0 g, 413 mmol) in methanol (300 mL). The mixture was stirred at room temperature for 3 days and concentrated in vacuo. The residue was dissolved in ether (300 mL), washed with water (2×150 mL), brine (150 mL), dried with Na2SO4, and concentrated in vacuo to afford 62.8 g (99%) of methyl 3-fluorobenzenecarboximidoate. Methylhydrazine (21.8 mL, 410 n mmol) was added to a stirred solution of methyl 3-fluorobenzenecarboximidoate (62.8 g, 410 mmol) in THF (350 mL). The mixture was stirred at room temperature for 3 days, then. Then methyl 2,2-diethoxyethanimidoate (66.1 g, 410 mmol) and acetic acid (37.5 mL, 656 mmol) were added. The mixture was stirred for 24 h. The reaction was diluted with CH2Cl2 (500 mL), and the formed precipitate was filtered off. The filtrate was washed with 10% citric acid (2×200 mL), water (300 mL), brine (200 mL), dried with Na2SO4, and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel using 1% MeOH/CHCl3 as eluent to give 24.0 g (21%) of the title product.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[H-]>C1COCC1.C1(C)C=CC=CC=1>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:3]([CH3:5])([CH3:4])[C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: CC(C)(C#N)c1ccc(C#N)cc1
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
4-(1-cyano-1-methylethyl)benzonitrile (2.28 g, 13.41 mmol) is dissolved in dry THF and the solution cooled to 0° C. Red-A1 (85% soln in toluene, 2.62 ml, 13.41 mmol of hydride) is added and the reaction stirred at 0° C. for 4 hours. The mixture is quenched with methanol and concentrated under vacuo. The residue is dissolved in CH2Cl2, washed with 2 portions of water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude is purified by normal phase MPLC (SiO2, DCM to DCM/MeOH 3:1), giving 2-[4-(aminomethyl)phenyl]-2-methylpropanenitrile (900 mg, 5.17 mmol, 39%) as a colorless oil. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.68 (s, 6H) 4.00-4.05 (m, 2H) 7.55 (q, J=8.59 Hz, 4H) 8.35 (broad s, 2H).