Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=2)([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Yield: 38.7 %

Procedure:
To a solution of 1-bromo-3,4-difluorobenzene (4 g, 20.7 mmol) in dry diethyl ether (25 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 8.3 mL, 20.7 mmol). The mixture was stirred at −78° C. for 1 h after which a solution of 1-benzylpyrrolidin-3-one (3.62 g, 20.7 mmol) in dry diethyl ether (15 mL) was added drop wise. The mixture was stirred at −78° C. for 15 min and at ambient temperature for 1 h after which aqueous saturated ammonium chloride solution (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification twice by flash chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1 and 3:2 isocratic) gave the title compound (2.32 g). MS m/z (relative intensity, 70 eV) 289 (M+, 4), 198 (23), 133 (29), 132 (23), 91 (bp). The enantiomers were separated by chiral HPLC (Kromasil 5-Cellucoat, heptane/2-propanol/diethyl amine, 99:1:0.1). Yield: enantiomer E1, 0.81 g, enantiomer E2 0.835 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[OH-].[Li+].S([O-])(O)(=O)=O.[K+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]3)=[CH:7][CH:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)ccn1
Temperature: 85 °C
Yield: 99.8 %

Procedure:
A mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 2.00 g, 5.07 mmol), ethyl piperidine-4-carboxylate (1.2 g, 7.61 mmol), sodium tert-butoxide (975 mg, 10.1 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl (484 mg, 1.01 mmol) and tris(dibenzylideneacetone)dipalladium(0) (464 mg, 507 μmol) in toluene (100 mL) was heated at 85° C. for 4 h and at room temperature for 17 h, then filtered through diatomaceous earth. After evaporation of volatile material, the residue was dissolved in tetrahydrofuran (50 mL), 1 M aq. lithium hydroxide solution (50 mL, 50 mmol) and methanol (15 mL), then after 2 h treated with 1 M aq. potassium hydrogensulfate solution (40 mL) and sat. aq. ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; dichloromethane-methanol gradient) produced the title compound (2.24 g, 66%). Light yellow solid, MS (ESI−): m/z=441.3 ([M−H]−).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11](OC)OC)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)([O-:18])=[O:17].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH:10]=[CH:11][N:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)[C:26]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(CNCCCC1CCCC1)OC
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1n(CCCC2CCCC2)ccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The product from Example 48 (2.6 g, 12.1 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to 0° C. 4-Nitrophenylisocyanate (1.98 g, 12.1 mmol) was added, and the mixture was allowed to warm to 23° C. The reaction was diluted with additional CH2Cl2 (30 mL) and cooled to 0° C. before a 1:1 solution of trifluoroacetic acid and water was added. The biphasic solution was vigorously stirred for 18 hours at ambient temperature. The layers were separated, and the aqueous layer was extracted with CHCl3. The combined organic layers were washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated to a yellow solid. Mp 105-107° C. Rf=0.4 (2:1 hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, 2H), 8.11 (d, 2H), 7.26 (d, 1H), 6.91 (d, 1H), 3.57 (t, 2H), 1.71 (m, 3H), 1.63 (m, 2H), 1.47 (m, 4H), 1.24 (m, 2H), 1.03 (m, 2H); MS (CI) m/z 316 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)[CH3:4].ClS([N:20]=[C:21]=[O:22])(=O)=O.C(O)(=O)C>C1COCC1.O>[CH2:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]=[O:15])=[CH:10][N:11]2[C:21]([NH2:20])=[O:22])=[CH:7][CH:6]=1)[CH3:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCc1ccc2c(C=O)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc2c(C=O)cn(C(N)=O)c2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (60% in mineral oil, 259 mg, 6.47 mmol) in THF (10 mL) cooled to 5° C. under nitrogen a solution of 6-ethyl-1H-indole-3-carbaldehyde (1.12 g, 6.47 mmol) in THF (20 mL) was slowly added and the mixture was stirred at 5° C. for 30 min. While maintaining the internal temperature between 5° C. and 10° C., chlorosulfonyl isocyanate (1.12 mL, 12.9 mmol) was added dropwise and the solution was further stirred at RT overnight. Acetic acid (15 mL) was added (slightly exothermic) and the solution was stirred at RT for 1.5 h. Ice cubes and water (25 mL) were added, and the solution was further stirred at RT for 30 min. Water was added and the mixture was extracted with EtOAc. The aqueous layer was back-extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to EtOAc) to give the desired compound. LC/MS: 290.0 [M+H]+, 312.0 [M+Na]+; tR (HPLC conditions a): 3.02 min.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([CH3:13])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.C(O)C.[Cl:18][C:19]1[C:20]([NH:26][NH2:27])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[N:27][N:26]([C:20]2[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=2)[C:11]=1[CH3:13])=[O:7])[CH3:10]
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ncc(Cl)cc2Cl)c1C

Procedure:
To ethyl 2-(ethoxymethylene)acetoacetate (25.1 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added 1N hydrochloric acid aqueous solution (135 ml) and an ethanol solution (135 ml) of 3,5-dichloropyridin-2-ylhydrazine (24.02 g) described above, stirred at reflux temperature for three hours and left to stand at room temperature. Water was added to the reaction solution, the precipitated solid was collected by filtration and purified with a mixed solvent of ethyl acetate and n-hexane to give 1-(3,5-dichloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [H-].[Na+].COCCO[Al+]OCCOC.[H-].[CH2:15]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=O)[CH2:29][CH2:28]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+]>CC1C=CC=CC=1>[CH2:15]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([CH3:37])([CH3:38])[CH2:34][NH2:36])[CH2:31][CH2:32]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCN1CCC(C(C)(C)C(N)=O)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN1CCC(C(C)(C)CN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
10 ml of bis(2-methoxyethoxy)aluminium-sodium hydride was added dropwise to a solution of 2.95 g (8.7×10-2 mole) of 1-dodecyl-α,α-dimethyl-4-piperidine-acetamide in 80 ml of methylbenzene. After stirring for one hour at room temperature, the mixture was refluxed for three hours. After cooling the mixture, 50 ml of 3N sodium hydroxide was carefully added and stirring was continued for 24 hours. The resulting mixture was extracted with methylbenzene. The organic phase was washed with water, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. The product was purified using silica gel chromatography, eluting with a 4/1/0.1 (v/v/v) ethyl acetate/methanol/ammonia mixture. 1.8 g (yield: 64%) of 1-dodecyl-β,β-dimethyl-4-piperidineethanamine was obtained as an oil. The (E)-2-butenedioate was obtained from this oil in an acetone-ether mixture. M Pt=100°-120° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]2[CH:16]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1.O>[C:14]([C:12]1[CH:11]=[CH:10][N:9]2[CH:16]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]2[CH:13]=1)#[N:15]
Reactant: CCOC(=O)c1cn2ccc(C#N)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccn2cc(C(=O)O)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (501 mg, 2.33 mmol) in 5:1 dioxane/water (30 mL) add sodium hydroxide (130 mg, 3.26 mmol) and stir at 50° C. overnight. Concentrate to a solid and acidify with 4 M HCl in dioxane. Concentrate again to afford the desired product 7-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid and use without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:17])[C:14]([NH2:16])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:11][C:9]1[CH:10]=[CH:2][C:3]([O:18][CH3:19])=[C:4]2[C:8]=1[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:17])[CH2:14][NH2:16]
Reactant: COc1c(Br)cc(F)c2c1c(C(C)C(N)=O)cn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c2c1c(C(C)CN)cn2C
Yield: 27.6 %

Procedure:
To the solution of 9-4 (154 mg, 0.46 mmol) in anhydrous THF (10 mL) was added LiAlH4 (53 mg, 1.40 mmol). The mixture was heated to reflux for 2 h. Na2SO4.10H2O was added and the solid was filtered off. The filtrate was concentrated in vacuo to get a residue, which was purified by preparative TLC (DCM:MeOH:10:1) to afford compound 9-5 (30 mg, 27% yield) as white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[C:4]([N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)=[CH:15][N:16]([CH3:18])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)C(=O)Cn1cncn1
Product: CN(C)C=C(C(=O)C(C)(C)C)n1cncn1
Yield: 91.8 %

Procedure:
250.8 g (1.5 mol) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 196 g (1.65 mol) of dimethylformamide dimethyl acetal were heated under reflux for 5 hours. Thereafter, the excess acetal was distilled off. 306 g (92% of theory) of 4,4-dimethyl-1-dimethylamino-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of refractive index nD20 1.531 were obtained. ##STR14##
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:10]1[N:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[C:12](=[O:20])[C:13]2[CH2:19][CH2:18][CH2:17][NH:16][C:14]=2[N:15]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([C:10]1[N:11]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=2)[C:12](=[O:20])[C:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:40](=[O:42])[CH3:41])[C:14]=2[N:15]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(-n2c(C(C)NC(=O)OC(C)(C)C)nc3c(c2=O)CCCN3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-n2c([C@@H](C)NC(=O)OC(C)(C)C)nc3c(c2=O)CCCN3C(C)=O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
D2 (263 mg, 0.63 mmol) and N,N-diisopropylethylamine (111 μL, 0.63 mmol) were dissolved in acetic anhydride (10 mL) and heated to 80° C. The reaction stirred overnight. It was quenched with saturated aqueous sodium bicarbonate, then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, concentrated in vacuo. Purified by chromatography (1:1 to 1:2 hexane:ethyl acetate), recovering 168 mg of D3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([Cl:30])=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(Cl)c1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-chloro-5-methoxybenzoic acid (541 mg), toluene (5.4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (578 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[O:21][CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3OC)c(F)ccc2c1N
Yield: 52.8 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (250 mg, 0.67 mmol) and (2-methoxy-4-fluorophenyl)boronic acid (227.1 mg, 1.336 mmol) were reacted to afford the title compound (131.7 mg, 53% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.49 (bs, 1H), 7.89 (d×d, J=5.5 Hz, J=9.2 Hz, 1H), 7.52 (apparent triplet, J=8.9 Hz, 1H), 7.30 (m, 1H), 6.82 (d×d, J=2.4 Hz, J=8.5 Hz, 1H), 6.79 (d×d, J=2.4 Hz, J=12.8 Hz, 1H), 3.72 (s, 3H), 3.44 (q, J=6.7 Hz, J=13.4 Hz, 2H), 1.64 (apparent sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.6 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.70 min.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:37])[NH:30][C:31]3[C:36]\2=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:44]>ClCCl>[ClH:44].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:37])[NH:30][C:31]3[C:36]\2=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone and ethyl acetate/hydrogen chloride in dichloromethane.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>ClCCl>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: CC(C)CCOCc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(C)CCOCc1cccc(N)c1
Yield: 97.1 %

Procedure:
After condensing the filtrate together with the ethanol washings, the condensate was dissolved into 300 ml of dichloromethane and after washing the thus formed solution with an aqueous 10% sodium carbonate solution, then with an aqueous saturated sodium chloride solution, the thus washed solution was dried over anhydrous potassium carbonate. By distilling the solvent off from the thus dried solution and fractionally distilling the residue, 109.2 g of a fraction boiling at 105° to 106° C. (0.19 mmHg) were collected to obtain 3-[(3-methylbutoxy)methyl]aniline in a yield of 97.1%.
Reaction SMILES: O=C1CCCN1C1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[F:22][C:23]1[C:32]([N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:31][C:30]([N:39]2[CH2:43][CH2:42][CH2:41][C:40]2=[O:44])=[CH:29][C:24]=1[C:25]([O:27]C)=[O:26]>>[F:22][C:23]1[C:32]([N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:31][C:30]([N:39]2[CH2:43][CH2:42][CH2:41][C:40]2=[O:44])=[CH:29][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F
Agent: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F

Procedure:
Prepared in an analogous manner to D8 from methyl 2-fluoro-3,5-bis-(2-oxopyrrolidin-1-yl)benzoate (D39).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product. Purification by column chromatography over silica gel afforded the title compound (0.02 g, 20%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:13][C:9]=2[C:10]([CH3:12])=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: CCOC(=O)c1nc(C)c2sc(-c3ccccc3)nc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2nc(-c3ccccc3)sc12
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 7-hydroxy-4-methyl-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (105 mg, 0.33 mmole) and glycine (500 mg, 6.65 mmole) in 0.5 M sodium methoxide/methanol (12.6 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 ml) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (25 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.08 (br s, 1H), 9.22 (t, 1H), 8.13 (m, 2H), 7.61 (m, 3H), 4.02 (d, J=6.2 Hz, 2H), 2.72 (s, 3H); MS: (+) m/z 344.26 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8](=O)[N:9]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[NH:11][C:12]=1[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:8]1[C:7]([Cl:6])=[C:12]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[N:11]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[N:9]=1
Reactant: CCOC(OCC)c1[nH]c(C2CC2)nc(=O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
Phosphorus oxychloride (35.1 g, 0.229 mol) in toluene (93 mL) was added to 5-chloro-2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone (i.e. the product of Example 4) (51.75 g, 0.190 mol) and N,N-dimethylformamide (34.7 g, 0.475 mol) in toluene (186 mL) at −5 to 0° C. The mixture was allowed to warm to room temperature over about 2 h. Then the mixture was added to aqueous sodium carbonate solution (saturated, 600 mL). The aqueous phase was further extracted with ethyl acetate (4×50 mL), and the organic extracts were combined, dried and evaporated to leave the product as an oil (52.9 g, 95% yield).
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[NH2:42][CH2:43][C:44]([NH2:46])=[O:45]>>[NH2:46][C:44](=[O:45])[CH2:43][NH:42][C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Reactant: NCC(N)=O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CC(=O)NCC(N)=O)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and glycineamide were reacted to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([Cl:30])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][OH:34].Cl>>[ClH:30].[NH2:31][CH2:32][CH2:33][O:34][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: NCCO
Agent: Cl
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN)c1

Procedure:
After treating 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide and 2-aminoethanol in the same manner as in Example 1, the precipitated crystals are converted into a hydrochloride thereof to give N-{6-(2-aminoethoxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide hydrochloride (Compound A).