Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:14]>O=S(Cl)Cl.C1COCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCC1CCCCC1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)CCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of cyclohexanepentanoic acid (2 g, 10.9 mmol) in SOCl2 (8 mL) was heated on a steam bath for 3 h. The SOCl2 was removed under vacuum. Chloroform (2×10 mL) was added and reevaporated to give the crude acid chloride as a yellow liquid. A saturated solution of ammonia in dry THF (ammonia gas bubbled through 10 mL of THF for 5 min), was slowly added to a solution of the acid chloride in dry THF (50 mL) while cooling in an ice bath. The reaction mixture was allowed to stir at room temperature for 3 h and was then concentrated to half of its volume and poured onto water (100 mL). The solid was removed by filtration, washed with water and dried (MgSO4). Recrystallization from aqueous MeOH gave 5-cyclohexylvaleramide (1.1 g, 55%); mp 121-122° C. (reported mp 122-123° C.) (Katsellson and Dubinin, Compt. Rend. Acad. Sci. U.R.S.S. [N.S.] 4:405 (1936); Chem. Abstr. 31:3449 (1937)). A suspension of the amide (183 mg, 1 mmol) in anhydrous Et2O (9 mL) was slowly added to a stirred suspension of LiAlH4 (114 mg, 3 mmol) in Et2O (15 mL). After addition was complete, the mixture was heated at reflux for 2 h and then allowed to stir overnight at room temperature. The reaction mixture was cooled to 0° C. and excess LiAlH4 was decomposed by successive addition of water (2 mL), 2N NaOH (2 mL) and water (5 mL). After stirring vigorously for 20 min, the mixture was filtered and the inorganic residue was washed with warm Et2O (3×8 mL). The combined Et2O solution was dried over anhydrous K2CO3 and evaporated to dryness. The residue was distilled under reduced pressure to yield a clear oil (99 mg, 59%); bp 30-36° C. (0.35 mm), Lit. bp 108≥113° C. (15 nm) (Skinner, C. G., et al., J. Am. Chem. Soc. 79:2844 (1957)). A solution of the free base in anhydrous Et2O was added to a solution of oxalic acid (52 mg) in anhydrous Et2O (8 mL) with continuous shaking. The precipitated solid was recrystallized from MeOH/anhydrous Et2O; mp 164° C. (see Table 8).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:8]2[N:9]=[CH:10][C:11](Br)=[CH:12][N:7]2[N:6]=1)=[O:4].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:8]2[N:9]=[CH:10][C:11]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][N:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1
Product: COC(=O)c1cc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, grey solid, MS: m/e=278.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (example 28, step 1) and phenylacetylene.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O:11][CH2:12][CH3:13]>C1C=CC=CC=1>[C:1]1([CH:3]2[CH2:2][CH:1]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:6][CH2:13][C:12]2=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Solvent: c1ccccc1
Product: O=C1CCC(c2ccccc2)CC1c1ccccc1

Procedure:
The oil was dissolved in 400 mL benzene and added dropwise over 40 minutes to 83 mL (250 mmol) of a 3.0M solution of phenylmagnesium bromide in ether, cooling so the temperature did not rise above 10° C. The reaction was then allowed to warm and heated to reflux for 14 hours. It was then cooled, quenched with aqueous ammonium chloride solution, then washed with water and brine, dried over sodium sulfate, and evaporated. The yield was 53.9 g (approximately theoretical), and the crude oil was used directly in the next step.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].Cl.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=1)#[N:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CNC(=NCc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and a solution of p-nitrobenzylamine hydrochloride (0.55 2.9 mmol) and triethylamine (0.32 g, 3.2 mmol) in methanol (5 ml) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.70 g, 2.5 mmol, yield: 95%) as colorless powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:19]=[CH:18][N:17]=[C:16]([C:20]3[C:21]([C:27]([F:30])([F:29])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[N:19]=[CH:18][N:17]=[C:16]([C:20]3[C:21]([C:27]([F:28])([F:30])[F:29])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A portion of 3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide (1.269 g, 3 mmol) was taken up in dichloromethane (25 mL). The to yellowish solution was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours and then carefully poured into ice-water (100 mL) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. Recrystallisation from a dichloromethane-ethanol mixture gave 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide as a yellow solid, 1.07 g (90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH3:12])[C:3]=1[C:13]([F:16])([F:15])[F:14].C(O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:12])[C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc(Br)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a mixture of N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g) and ethanol (40 mL) was added concentrated hydrochloric acid (40 mL) at room temperature. The reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was left to be cooled to room temperature, and ethyl acetate and water were added thereto, followed by alkalification with potassium carbonate. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-60:40) to obtain 4-bromo-2-methyl-3-(trifluoromethyl) aniline (6.9 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH2:13].[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH:13][C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][N:20]=1)=[O:23]
Reactant: Cc1ccc(C(=O)O)nc1
Reactant: COC(=O)c1ccc(OC)c(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccc(C)cn1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
2-Amino-4-methoxy-3-methyl-benzoic acid methyl ester (400 mg, 2 mmol) and 5-methyl-pyridine-2-carboxylic acid (280 mmol, 2 mmol) where dissolved in dichloro-methane (8 ml) and pyridine (1 ml). Phosphorous oxychloride (0.37 ml) was added while cooling on ice-bath. The mixture was left at 0° C. for 1 h then allowed to attain room temperature. Aqueous sodium hydroxide (20 ml, 1M) was added and the mixture were extracted with dichloromethane. Purification by column chromatography on silica gel (ether-pentane 1:1) gave pure title compound (410 mg, 65%). MS (M−H)+ 315.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]([NH:13][C:14](=O)[CH3:15])[CH2:10]C=C.II.[C:19]([O-:22])(O)=[O:20].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].[CH2:31]1COCC1>O>[C:19]([O:22][CH:15]1[CH2:10][C@H:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Br:1])[NH:13][CH2:14]1)(=[O:20])[CH3:31]
Reactant: C1CCOC1
Reactant: C=CC[C@@H](NC(C)=O)c1cc(F)ccc1Br
Reactant: O=C([O-])O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CC(=O)OC1CN[C@@H](c2cc(F)ccc2Br)C1
Reaction time: 6 h

Procedure:
To a solution of (R)-N-(1-(2-bromo-5-fluorophenyl)but-3-en-1-yl)acetamide (I-46) (1.50 g, 5.24 mmol) in THF (12 mL) was added water (3 mL) followed by iodine (4.0 g, 15.7 mmol). After stirring 6 hours the reaction mixture was poured into a mixture of saturated aqueous NaHCO3 (30 mL) and saturated aqueous Na2S2O3 (25 mL), extracted with EtOAc (2×40 mL), washed successively with saturated aqueous Na2S2O3, water and brine, dried over sodium sulfate and concentrated to dryness to give (5R)-5-(2-bromo-5-fluorophenyl)pyrrolidin-3-yl acetate (I-47) as a pale amber oil, which was used without purification in the next step. MS m/z 302.0, 304.0 (M+1)+.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].COC(C)(C)C>C(N(CC)CC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:7]1[C:2]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: C#CCCO
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: OCCC#Cc1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of 1-bromo-2,3,4,5,6-pentafluorobenzene (50 g) in triethylamine (200 mL), 3-butyn-1-ol (15 g), triphenylphosphine (2.7 g), dichlorobistriphenylphosphinepalladium (3.6 g) and copper (I) iodide (1.9 g) were added, followed by stirring at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, and tert-butyl methyl ether (500 mL) was added thereto, followed by stirring at 0° C. for 30 minutes. The reaction mixture was filtered through Celite®, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (hexane:ethyl acetate=95:5→65:35) to give the title compound (43 g) having the following physical properties.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH2:12])[CH:6]=1.CC(O)=O.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>ClC(Cl)C.CO>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1cccc(CN)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(CNCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
Suspended 3-aminomethyl-benzoic acid methyl ester hydrochloride (100 mg. 0.99 mmol) in 3 mL of dichloroethane in a microwave tube and added 100 uL of AcOH. To this was added benzaldehyde (0.10 mL, 1.00 mmol). The mixture was sealed and heated at 120° C. for 20 minutes resulting in a homogeneous solution. 2 mL of MeOH was added and the mixture was treated with NaBH4 (56.8 mg, 1.50 mmol) resulting in gas evolution. The mixture stirred for 19 h. The mixture was quenched with careful addition of 5% HCl resulting in a bi-phasic mixture. The aqueous phase was removed and treated with 50×2-200 Dowex acidic ion exchange resin. The product was liberated with 10% NH3 in MeOH and concentrated to give 197 mg of 3-(benzylamino-methyl)-benzoic acid methyl ester, partially contaminated with starting benzyl amine (15%).
Reaction SMILES: CN1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8]([O:12][CH2:13][C:14]1C=C[CH:17]=[CH:16][CH:15]=1)(=[O:11])C#C.C1C[O:23]CC1>>[CH2:8]1[O:11][C:7]2[C:13](=[CH:14][CH:15]=[C:16]3[C:6]=2[O:5][CH2:4][CH2:3][C:17]3=[O:23])[O:12]1
Reactant: CN1CCOCC1
Reactant: C#CC(=O)OCc1ccccc1
Reactant: C1CCOC1
Product: O=C1CCOc2c1ccc1c2OCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-methylenediexyphenol (27 g) and N-methyl morpholine (19.6 g) in THF (100 ml) was added benzyl propiolate (38 g) over a period of 30 minutes with cooling. After the addition was complete the reaction was stirred at room temperature for 1.5 hours followed by concentration. The residue was taken up into Et2O (500 ml), washed with 10% HCl (2×100 ml), dried over MgSO4, filtered and concentrated. This material was subjected to hydrogenation with 10% Pd/C in methanol at 4 atm. The reaction was filtered and concentrated. The resulting saturated acid was dissolved into methanesulfonic acid (350 ml) and stirred for 24 hours. The reaction was poured onto ice and extracted with CH2Cl2. The organic layer was washed with saturated Na2CO3, dried over MgSO4, filtered and concentrated to provide the desired material.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>C1COCC1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:19]#[N:20])[CH2:21][CH:23]2[CH2:24][OH:25])=[CH:14][CH:13]=1
Reactant: ClCC1CO1
Reactant: N#CCc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cc2)CC1CO
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of NaHMDS (23 g, 127.5 mmol) in THF (80 mL), was added a solution of 4-bromophenylacetonitrile (10 g, 51.0 mmol) in THF (80 mL) at −10° C. and stirred for 10 min. Epichlorohydrin (4.7 mL, 56.11 mmol) was added to the reaction mixture at −10° C. and then stirred the mixture at r.t. for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with 2:1 dioxane:hydrochloric acid (10 mL) at 0° C. and extracted with diethyl ether (3×200 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated to yield the title compound (12.8 g, 100%) as brown oil which was used as such in the next step.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-])=O)=[CH:10][C:11]=3[F:13])[CH2:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:14][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([F:13])[CH:10]=1)[N:4]([CH:1]1[CH2:2][CH2:3]1)[C:5](=[O:17])[CH2:6]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(F)c2c(c1)CC(=O)N2C1CC1
Temperature: 25 °C

Procedure:
Iron powder (0.994 g, 17.8 mmol) is added in small portions to 1-cyclopropyl-7-fluoro-5-nitro-1,3-dihydro-indol-2-one (1.05 g, 4.44 mmol) and ammonium chloride (2.32 g, 44.5 mmol) in ethanol (50 ml) and water (25 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 60 min, cooled to room temperature, and diluted with dichloromethane (250 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a yellowish-brown solid. HPLC r.t. 2.62 min; MS for C11H11FN2O m/z 207.2 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:30]([O:32][CH2:33][CH2:34][OH:35])[CH3:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([O:35][CH2:34][CH2:33][O:32][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Reactant: CCOCCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCCOCC)cc1

Procedure:
Prepared as described in Example 18, 10.0 g. of 4-(hexadecylamino)hydrocinnamoyl chloride hydrochloride in 80. ml. of methylene chloride is treated with 9.5 g. of 4-dimethylaminopyridine and 2.1 g. of 2-ethoxyethanol, analogous to the method of Example 19. Workup and filtration through alumina provides 2-ethoxyethyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][NH:15][C:12]2=[CH:13][N:14]=1.[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([CH2:33][CH3:34])[N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[Cl:25][C:26]1[N:31]=[C:30]([N:15]2[C:12]3=[CH:13][N:14]=[C:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[CH:10]=[C:11]3[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16]2)[CH:29]=[C:28]([CH2:33][CH3:34])[N:27]=1
Reactant: CCc1cc(Cl)nc(Cl)n1
Reactant: CCC(CC)C(=O)c1c[nH]c2cnc(-c3c(C)cccc3C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(-n2cc(C(=O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-[5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (200 mg, 0.62 mmol), 2,4-dichloro-6-ethyl-pyrimidine (221 mg, 1.25 mmol), Cs2CO3 (305 mg, 0.93 mmol), and DMF (3 mL) is stirred for 4 h at room temperature. The mixture is diluted with EtOAc (10 mL), and the obtained solution is washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one as colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6](CBr)=[CH:5][C:4]=1[Cl:11].[N-:12]=[N+]=[N-].[Na+].C[N:17]([CH3:20])C=O>O>[NH2:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:20][NH2:17])=[CH:5][C:4]=1[Cl:11]
Reactant: Clc1cc(CBr)ccc1CBr
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: NCc1ccc(CN)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The starting material 4-aminomethyl-3-chloro-benzylamine was prepared from 1,4-bis-bromomethyl-2-chloro-benzene as follows. A suspension of 1,4-bis-bromomethyl-2-chloro-benzene (470 mg) and sodiumazide (225 mg) in dimethylformamide (2.5 ml) was stirred at 60° C. for 2 hours. The reaction mixture was then diluted with water and extracted with ether. The combined organic extracts were then washed with water, dried (Na2SO4) and evaporated. Part of the remaining residue (233 mg) was dissolved in methanol (5 ml) and tin(II) chloride (962 mg) was added portionwise at 0° C. The reaction mixture was then stirred at room temperature over night. The solvent was removed and the residue was dissolved in 3N sodium hydroxide (12 ml) and this solution was saturated with sodium chloride and extracted with chloroform. The combined extracts were dried (sodium sulfate) and evaporated and the remaining material was purified by chromatography (dichloromethane/methanol/ammonia 19:1:0.1 and 9:0.9:0.1). 4-Aminomethyl-3-chloro-benzylamine was obtained as light yellow oil (76 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49](=[O:50])[CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 480.4 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.0103 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (0.018 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) in a similar manner as described herein to afford crude 1,1-dimethylethyl {2-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-2-oxoethyl}carbamate (0.031 g) as an off-white solid. This material was treated with trifluoroacetic acid (0.30 mL, 3.89 mmol) in dichloromethane (1 mL) for 1 h. The solvent was evaporated to give the title compound (0.011 g, 40%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ ppm 11.60 (s, 1H), 10.23 (s, 1H), 8.97 (s, 1H), 8.04 (m, 3H), 7.91 (s, 1H), 7.77 (s, 1H), 7.40-7.54 (m, 2H), 7.29-7.40 (m, 2 H), 7.17-7.27 (m, 1H), 7.10 (s, 1H), 4.60 (s, 2H), 3.72 (s, 2H). MS: m/z 526 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C.[Pd]>[CH3:16][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=C(C(=O)OCC)c1cnccc1N(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1cnccc1N(C)C

Procedure:
To a solution of the product of step iii) (3.6 g) in absolute ethanol (100 ml) was added 5% palladium/charcoal catalyst, and the mixture hydrogenated at ambient temperature and pressure until the theoretical volume of hydrogen had been consumed. The catalyst was removed by filtration through celite and the filtrate evaporated to yield ethyl 2-(4-dimethylamino-3-pyridyl)propanoate as a pale yellow oil (3,1 g) NMR (d6DMSO) δ 1.15(3H,t); 2.65(2H,t); 2.8(6H,s); 2.9(2H,t); 4.05(2H,q); 6.8(2H,d); 8.2(2H,d); m/e 223 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxyphenol (18.34 g) in tetrahydrofuran (150 ml) was added 60% sodium hydride (4.76 g) with ice-cooling, and the mixture was stirred at the same temperature for 15 min. Ethyl bromoacetate (14.2 ml) was added dropwise, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, 5% hydrochloric acid was added and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained solid was filtrated with hexane and dried under reduced pressure to give the title compound (21.78 g) as a white solid.