Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][O:10]/[C:11](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)/[C:12]([O:14][CH3:15])=[O:13].O>CN(C)C=O>[CH2:1]([NH:8][C:30](=[O:31])[N:29]([C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17](/[CH:16]=[C:11](\[O:10][CH3:9])/[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Reactant: CCCCCCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
0.6 mL (3.9 mmol) of heptylamine is added to a solution of 1.7 g (3.2 mmol) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate (prepared according to Example 11e) in 10 mL of dimethylformamide and the reaction medium is then placed in a bath preheated to 80° C. After stirring at 80° C. for 3 hours, water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 1.1 g (80%) of methyl (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate are obtained in the form of a white solid with a melting point of 93° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH:11][NH2:12])[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc(C)c(Cl)cc1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(Cl)cc1NN
Yield: 33.2 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-chloro-5-methyl-2-aminoanisole (10.26 g), NaNO2 (4.5 g), and SnCl2.2H2O (30 g). Workup gave 3.7 g (33%) of (5-chloro-4-methyl-2-methoxyphenyl)hydrazine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:9]1([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccnc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Brc1ccnc(-c2ccccc2)c1
Yield: 43.3 %

Procedure:
A mixture was prepared of 2,4-dibromopyridine (10 g, 42.21 mmol), phenylboronic acid (5.1 g, 42.21 mmol), and potassium carbonate (11.7 g, 84.42 mmol) in 100 mL dimethoxyethane and 40 mL of water. Nitrogen was bubbled directly into the mixture for 30 minutes. Next, tetrakis(triphenylphosphine)palladium(0) was added (244 mg, 2.11 mmol) and the mixture was heated to reflux under nitrogen overnight. The mixture was cooled and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes. Obtained 4.28 g of a yellow liquid (43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=2.[NH2:17][CH2:18][CH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:17][CH2:18][CH2:19][OH:20])=[CH:9][CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=2
Reactant: FC(F)(F)c1ccc2c(Cl)c(Br)cnc2c1
Reactant: NCCO
Solvent: CC(C)O
Solvent: O
Product: OCCNc1c(Br)cnc2cc(C(F)(F)F)ccc12

Procedure:
A solution of 12.4 g of 3-bromo-4-chloro-7-trifluoromethylquinoline and 6.1 g of 2-aminoethanol in 30 ml of isopropanol was heated at reflux for 4 hours. The mixture was cooled and diluted with 150 ml of water and the solid was collected and recrystallized from isopropanol. The yield was 8.2 g, mp 140°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([OH:52])=[O:51])[CH2:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([OH:52])=[O:51])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c3ccccc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(C(=O)NC(CCC(=O)O)C(=O)O)c3ccccc3n2)CC1
Yield: 97.3 %

Procedure:
Alternatively, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-carboxy-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (136 mg, 0.187 mmol) was treated with trifluoroacetic acid:methylene chloride (1:1, 1.2 mL) at ambient temperature for 1 hour. The solvents were evaporate and resulting residue diluted with methylene chloride, followed by evaporation of the solvent gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-[(1,3-dicarboxypropyl)aminocarbonyl]quinoline (112 mg); NMR (CD3OD) 1.20 (m, 3), 1.90 (m, 1), 2.10 (m, 2), 2.30–2.50 (m, 5), 3.40–3.80 (m, 8), 4.10 (m, 2), 4.70 (m, 1), 5.18 (m, 1), 7.60 (m, 1), 7.80 (m, 1), 8.20 (m, 3) ppm.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44](C)[CH2:45][OH:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([CH2:36][CH2:39][O:4][CH2:44][CH2:45][OH:46])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: C[C@@H](N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCOCCO)c4)cc23)CC1
Yield: 38.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting 2-[(2-aminoethyl)oxy]ethanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 17.2 mg of the title compound (38.7%).
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[Cl:15][C:16]1[CH:46]=[CH:45][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([C:30](=[O:44])[C:31]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[CH:37]4)=[O:32])=[CH:22]2)=[CH:18][CH:17]=1.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([C:30](=[O:44])[C:31]([N:33]([C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[CH:37]4)[C:12](=[O:14])[CH3:13])=[O:32])=[CH:22]2)=[CH:45][CH:46]=1
Reactant: O=C(Nc1ccc2ncccc2c1)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(C(=O)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.833 g (6.82 mMol) of DMAP, 1.38 g (13.6 mMol) of triethylamine and 13.9 g (136 mMol) of acetic anhydride are added, under nitrogen, to a stirred solution of 6.0 g (13.6 mMol) of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinolin-6-ylacetamide in 60 ml of DMF. The reaction mixture is stirred at room temperature for 10 minutes and, after that, poured into 200 ml of ethyl acetate. After 300 ml of water have been added, the mixture is shaken in a separating funnel after which the two phase separate. Precipitation begins after 20 minutes. The pale yellow crystals are filtered off and dried in vacuo at 60° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[C:10](/[CH:22]=C/C2C=CC=CC=2)[O:9][N:8]=1.I([O-])(=O)(=O)=[O:31].[Na+].C(OCC)(=O)C.O>C(O)(C)(C)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:22]([C:10]1[O:9][N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:11]=1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)=[O:31]
Reactant: N#Cc1ccc(OCc2c(-c3ccccn3)noc2/C=C/c2ccccc2)nc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCc2c(-c3ccccn3)noc2C=O)nc1
Temperature: 120 °C
Yield: 37.5 %

Procedure:
A mixture of 6-[3-pyridin-2-yl-5-((E)-styryl)-isoxazol-4-ylmethoxy]-nicotinonitrile (0.57 g, 2 mmol), osmium(VIII) oxide solution (0.38 mL of a 2.5% solution in tert-butanol, 0.04 mmol), sodium metaperiodate (1.29 g, 6 mmol), benzyltriethylammonium chloride (0.14 g, 0.6 mmol) in dioxane (13 mL) and water (4.5 mL) was heated in a microwave for 45 min at 120° C. Extractive workup (ethyl acetate/water) was followed by drying of the organic phase over sodium sulfate and filtering. The solvent was evaporated and the residue was triturated with diisopropylether to afford the title compound (0.23 g, 51%) as a white solid. MS: m/e=307.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(N(CC)CC)C>C(O)CCC>[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-aminoindole (6.23 g, 47 mmol), bis(2-chloroethyl)amine hydrochloride (16.8 g, 96 mmol) and triethylamine (19 mL, 141 mmol) in butanol is heated at 100° C. for 8 hours, cooled to room temperature and concentrated in vacuo to give 9.46 g of 5-piperazin-1-yl-1H-indole.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]=[O:15])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: CNCCC=O
Reactant: Cc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CCC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-methylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])[CH:2]=1.[C:22](OC=C)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CC(C)=O>[C:22]([O:18][CH2:17][C@H:15]1[O:16][C@H:11]([O:10][C:3]2[CH:2]=[CH:1][C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=2)[C@H:12]([OH:21])[C@@H:13]([OH:20])[C@@H:14]1[OH:19])(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=[N+]([O-])c1ccc(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: C=COC(=O)CCCCCCCCCCCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 84.9 %

Procedure:
In 40 ml of acetone were suspended 0.3 g (1 mmol) of 4-nitrophenyl-α-D-glucopyranoside (manufactured by Tokyo Kasei Ind., Ltd.) as marketed, 0.85 g (3 mmol) of vinyl palmitate and 30 mg of Lipase B, and the suspension was reacted in a shaking apparatus at 25° C. for 1 day. After the enzyme was filtered off, the solvent was concentrated to afford a crude product in a white wax form, which was purified by silica gel chromatography (5% methanol-dichloromethane) to give 0.458 g of 4-nitrophenyl 6-O-palmitoyl-α-D-glucopyranoside in a white wax form. Yield 81%
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.C([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C1C2C(CCCC2)CCC1.Cl>C(O)C.[Cu].CC(C)=O>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC(C)=O
Solvent: C1CCC2CCCCC2C1
Product: CC(=O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 13.0 g of m-trifluoromethylphenyl bromide, 8.68 g of p-acetylaminoacetophenone, 14.5 g of potassium carbonate, 0.45 g of copper powder and 40 ml of decahydronaphthalene was stirred at reflux on an oil bath at 200° C., under argon for 64 hours. The mixture was then cooled, stirred with 200 ml of acetone, filtered and the filtrate evaporated to a semi-solid. Evaporative distillation gave a semi-solid which was dissolved in 150 ml of ethanol and 150 ml of concentrated hydrochloric acid and refluxed under argon for 30 minutes. The mixture was cooled, partially evaporated and partitioned between 50% saturated brine and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried and evaporated to a semi-solid. This semi-solid was purified by chromatography, giving 4'-[3-(trifluoromethyl)phenylamino]acetophenone which was then converted to the desired product by the procedure of Example 9, giving the product as a light amber solid, m.p. 180°-195° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:17]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.6 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (9.21 g, 75 mmol), potassium carbonate (56 g, 410 mmol) and 4-bromobutyric acid ethyl ester (12.9 mL, 90 mmol) in N,N-dimethylformamide (250 mL) was stirred vigorously for 16 hours at room temperature. The mixture was filtered and concentrated in vacuo to afford 19.6 g (100%) of 4-(4-formylphenoxy)butyric acid ethyl ester as an oil. 1H-NMR (DMSO-d6): δ 1.21 (3H, t), 2.05 (2H, p), 2.49 (2H, t), 4.12 (4H, m), 7.13 (2H, d), 7.87 (2H, d), 9.90 (1H, s). HPLC-MS (Method A): m/z=237 (M+1); Rt=3.46 min.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32](=[O:44])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[CH2:27][CH2:26]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>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>[CH3:13][CH:12]([N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32](=[O:44])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[CH2:27][CH2:26]3)=[CH:3]1)[CH3:14]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: CC(C)n1cc(Br)c2c(N)ncnc21
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: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)c2c(N)ncnc21
Temperature: 100 °C
Yield: 47.2 %

Procedure:
To 5-bromo-7-(1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 0.274 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (166 mg, 0.384 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes then added Pd(Ph3P)4 (317 mg, 0.274 mmol) and the vessel was capped. The reaction was then heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of DMSO and then purified by HPLC: (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 35% ACN/H2O, 0.1% TFA to 60% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and the mixture was extracted with EtOAc (3×15 mL). The organics were combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried to provide 7-(1-methylethyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (62 mg, 47.1% yield) as a white solid. LC-MS (ES) m/z=480.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.13 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 3H), 7.54 (s, 1H), 7.36 (s, 1H), 7.26 (d, J=8.08 Hz, 1H), 6.57 (br. s., 2H), 4.99 (quin, J=6.76 Hz, 1H), 4.28 (t, J=8.46 Hz, 2H), 4.04 (s, 2H), 3.23-3.28 (m, 2H), 1.47 (d, J=6.82 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]([Si:12](Cl)([CH3:14])[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:23]([Li])[C:22]([CH3:25])=[C:21]([CH3:26])[C:20]=1[CH3:27]>O1CCCC1>[C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]([Si:12]([CH3:14])([CH3:13])[C:22]2([CH3:25])[CH:23]=[C:19]([CH3:18])[C:20]([CH3:27])=[C:21]2[CH3:26])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C1C(C)=C(C)C(C)=C1C
Reactant: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1(C)C=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution consisting of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane (5.24 g) synthesized in the above described (3) and tetrahydrofuran (50 ml) was added tetramethylcyclopentadienyl lithium (2.73 g) at −35° C., and the mixture was warmed to room temperature during 2 hours and stirred further at room temperature for 10 hours.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[O:18]([CH2:25][C:26](=O)[C:27]([OH:29])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>>[C:27]([CH:26]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:25][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:29])=[O:28]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: O=C(O)C(=O)COc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(COc1ccccc1)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
As described in Example 5, condense 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and phenoxypyruvic acid (preparable from ethyl phenoxyacetate and diethyl oxalate, followed by acid catalysed hydrolysis and decarboxylation) with sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:31][CH2:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=2)[N:7]=1
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(Cl)nc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A solution of 5 g of 2,4-dichloro-6-methoxy-1,3,5-triazine in 50 ml of acetonitrile is cooled on an ice bath, 3.55 ml of DIPEA and then 5.13 g of 2-[4-(trifluoromethoxy)phenyl]ethanamine are added and the mixture is stirred for 30 minutes. The reaction mixture is partially concentrated under vacuum, an EtOAc/water mixture is added, the phases are separated by settling, the organic phase is washed with saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. The precipitate formed during the evaporation is drained by suction, washed with EtOAc and dried. 7.89 g of the expected compound are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[NH:12][C:13](=O)[C:8]=2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13]([Cl:25])=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C)c2c(=O)[nH]c(-c3ccccc3F)nc21
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCn1nc(C)c2c(Cl)nc(-c3ccccc3F)nc21
Yield: 55 %

Procedure:
1-Butyl-6-(2-fluoro-phenyl)-3-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (1.23 g, 4.1 mmole) was dissolved in phosphorous oxychloride (15 ml) and heated to reflux overnight. The excess phosphorous oxychloride was removed under vacuum, the residue was treated with ice water, the product was extracted into ethyl acetate, washed with water, saturated sodium chloride, then dried over sodium sulfate (anh.) and the solvent was removed to give the crude product. The product was chromatographed on silica gel eluting with chloroform to give 723 mg of purified product (yield: 55%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]=[O:13]>CCOCC.C1COCC1.CCOC(C)=O>[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc(F)ccc1Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A solution of PhMgBr (1M in THF, 2.60 mL, 2.60 mmol) was added dropwise to a −78° C. solution of 2-bromo-5-fluorobenzaldehyde (0.4742 g, 2.336 mmol) in Et2O (5 mL) and THF (1.3 mL), stirred for 15 minutes, allowed to warm to room temperature, stirred for 30 minutes, diluted with EtOAc, washed with water and saturated NH4Cl, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (0-10% Et2O/hexanes) to give 561.0 mg of the title compound as a clear gum. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (dd, 1H), 7.46 (dd, 1H), 7.21-7.36 (m, 5H), 7.10 (ddd, 1H), 6.21 (s, 1H), 5.88 (s, 1H).