Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]#[CH:11].C([Li])CCC.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21]2.Cl>O1CCCC1.CCCCCC.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>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10]#[C:11][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21]2
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2c1
Reactant: C#CC1=C(C)CCCC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc2cc(C#CC3=C(C)CCCC3(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.503 g (3.3916 mmol) 1,3,3-trimethyl-2-ethynylcyclohexene (G. Kobrich et al. Chem Ber., 1966, 99,689.) in 4 ml of dry tetrahydrofuran at 0 degrees C. under argon was added dropwise 2.1 ml of 1.6M (3.36 mmol) of n-butyllithium in hexane. This mixture was stirred at 0 degrees C. for 10 minutes, at room temperature for 10 minutes and cooled again to 0 degrees C. To this was added, via cannula, a solution of 0.480 g (3.52 mmol) fused zinc chloride in 4 ml of tetrahydrofuran with stirring at 0 degrees C. for 40 minutes and at room temperature for 5 minutes. A solution of 0.9186 g (3.29 mmol) of ethyl 6-bromo-2-naphthoate (Anderson, L. C. J. Am. Chem. Soc., 1943, 65,242.) in 5 ml of dry tetrahydrofuran was transferred by cannula into a suspension of 0.410 g (0.3584 mmol) tetrakis(triphenylphosphine)palladium in 5 ml of dry tetrahydrofuran and stirred for 5 minutes at room temperature. This mixture was then treated via cannula with the solution of alkynyl zinc and the resultant mixture stirred at room temperature for 18 hours. Ice and 30 ml of 3N HCl was added and the products extracted with 4×50 ml ether. The combined ether extracts were washed with saturated NaHCO3 and NaCl solution, dried (MgSO4) and concentrated to give a brown oil. This oil was purified by HPLC (Waters 6000; Partisil M-9 10/50; 2% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[CH:27]([NH2:31])([CH2:29][CH3:30])[CH3:28]>>[CH:27]([NH:31][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: CCC(C)N
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Product: CCC(C)NCc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1

Procedure:
According to the same manner as that described in Example 56, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline was reacted with sec-butylamine to give 2-(sec-butylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 118°-120° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19].C(OCC)(=O)C.CCCCCC>CN(C)C=O.O>[Br:1][C:2]1[C:7]([O:8][CH2:18][CH3:19])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cccc(O)c1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cccc(C(C)=O)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, 1-(2-bromo-3-hydroxy phenyl)ethanone (6.50 g, 30.2 mmol), which had been obtained in Reference example 3 (3c), and potassium carbonate (8.36 g, 60.5 mmol) were dissolved in N,N-dimethyl formamide (60 mL), and stirred at room temperature for 10 minutes. Subsequently, ethyl iodide (3.14 mL, 39.3 mmol) was added to the mixture, which was then further stirred for 21 hours. Ethyl acetate/hexane (1:1, V/V) and water were added to the reaction solution for fractionation, and the aqueous layer was extracted with ethyl acetate/hexane (1:1, V/V). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 100:0-85:15, V/V) to give the title compound as a colorless oily substance (4.89 g, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[OH-].[K+]>C(O)C.Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
A hot solution of 13 g (0.05 mol) of 4'-chloro-4-nitrobenzophenone in 80 ml of ethanol was added in small portions, while stirring, to a hot solution of 53.5 g (0.24 mol) of tin(II)chloride dihydrate in 50 ml of concentrated hydrochloric acid, which was accompanied by a violent reaction. After all had been added, the mixture was heated on a steam bath for two hours and was then poured into an aqueous potassium hydroxide solution, while stirring. A precipitate was formed which was suction-filtered off and dissolved in boiling ethanol. The insoluble matter was filtered off, and the filtrate was allowed to cool. The light yellow crystals which precipitated were suction-filtered off.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([O:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:14]=1[C:15]2=[O:20])[CH3:2].F[B-](F)(F)F.[O:34]=[N+:35]=[O:36]>C(Cl)Cl>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([O:21][CH2:22][CH2:23][CH3:24])=[C:13]([N+:35]([O-:36])=[O:34])[C:14]=1[C:15]2=[O:20])[CH3:28]
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OCCN(CC)CC)c1-2
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1cc(OC)c2c(c1[N+](=O)[O-])C(=O)c1cccc(OCCN(CC)CC)c1-2
Temperature: 25 °C
Yield: 41.8 %

Procedure:
Prepare a solution of 5-(2-diethylamino-ethoxy)-4-methoxy-2-propoxy-fluoren-9-one (1.1 g, 2.9 mmole) in 100 mL anhydrous methylene chloride at -72° C. under argon while stirring. Add nitronium tetrafluoroborate (0.42 g, 3.2 mmole) in one continuous portion. Allow the mixture to warm to room temperature for 3 hours while the solution darkens. Stir an additional 2 hours, then check reaction progress with an aliquot by thin layer chromatography. Quench the reaction with water and transfer to a seperatory funnel. Retain the organic layer and filter off an insoluble red solid from the interface. Wash with water and methylene chloride. Take up the solid into 5% sodium hydroxide and stir vigorously. Extract with methylene chloride and chromatotron the organics, combine the CH2Cl2 fractions and dry over MgSO4, filter and concentrate on the rotary evaporator. Chromatograph the resulting residue, eluting with methanol/CH2Cl2 (5:95) to obtain 0.52 g (52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:18]([Mg]Br)#[CH:19].O>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:10]([CH:11]([OH:12])[C:18]#[CH:19])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1c(-c2ccco2)nn2c(Cl)cccc12
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccco2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (3.36 g, 13.6 mmol) in tetrahydrofuran (100 mL) at −78° C. was added ethynylmagnesium bromide (32.7 mL, 0.5 M in tetrahydrofuran, 16.3 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated to a solid residue, 1-[(7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (3.63 g, 98%). 1H NMR (CDCl3): δ 7.98 (d, 1H), 7.59 (d, 1H), 7.16 (t, 1H), 7.03 (d, 1H), 6.95 (d, 1H), 6.55 (m, 1H), 6.16 (m, 1H), 2.76 (m, 1H), 2.63 (s, 1H). MS m/z 273 (M+1).
Reaction SMILES: [C:1]1([C:7]2([CH3:26])[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]3[C:9](=[C:10]([Cl:24])[C:11]([Cl:23])=[C:12]([OH:22])[CH:13]=3)[C:8]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37]CC)=[O:36].[OH-].[Na+].Cl>CN(C)C=O.O>[O:25]=[C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:22][CH2:34][C:35]([OH:37])=[O:36])=[C:11]([Cl:23])[C:10]=2[Cl:24])[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: CC1(c2ccccc2)C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 90 °C

Procedure:
A stirred mixture of 2,3-diphenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.24 g., 0.00585 mole), potassium carbonate (1.62 g., 0.0117 mole) and ethyl bromoacetate (1.96 g., 0.0117 mole) in dimethylformamide (100 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (100 ml.)-10 N sodium hydroxide solution (5 ml., 0.05 mole) and heated at 90° C. for 1.5 hours. The reaction mixture is added slowly to water (1 l.)-12 N hydrochloric acid (10 ml.) to precipitate 1.14 g. of (1-oxo-2,3-diphenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 203°-205° C. after crystallization from nitromethane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH4+].[Cl-]>C1COCC1.Cl[Pd]Cl.O>[CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1)=[CH2:12]
Reactant: Brc1ccc2ccsc2c1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2ccsc2c1
Temperature: 85 °C
Yield: 41 %

Procedure:
A mixture of 6-bromobenzo[b]thiophene (217 mg, 1.02 mmol), potassium vinyltrifluoroborate (137 mg, 1.02 mmol), Cs2CO3 (983 mg, 3.02 mmol), Ph3P (17 mg, 0.066 mmol) and PdCl2 (5 mg, 0.028 mol) in THF (1.8 mL)/H2O (0.2 mL) was heated at 85° C. After overhight stirring, H2O (5 mL) and saturated NH4Cl solution (50 mL) were added and the resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (67 mg, 41%).
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:25])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[C:19]1([C:16]2[C:17](=[O:18])[NH:8][C:9](=[O:25])[N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SCCC2
Reaction time: 0.5 h

Procedure:
To a solution of 17.52 g (50 mmol) of 7-benzyl-9-phenyl-3,4-dihydro-2H,6H-pyrimido-[6,1-b][1,3]thiazine-6,8(7H)-dione in 500 ml of toluene, 25 g (100 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 100 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 4.21 g (32.4%, light white crystal) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:13])[CH2:10]2)=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CC(N)CC2
Product: COc1ccc2c(c1)CC(NC(C)=O)CC2
Yield: 51 %

Procedure:
Using a procedure similar to that described in Example 1, 0.40 g of 7-methoxy-2-amino-tetralin yielded 0.21 g (51%) of 7-methoxy-2-acetamido-tetralin following treatment with acetic anhydride.
Reaction SMILES: ClC1C=C(C(N)C)C2OCOC=2C=1.FC1C=C(F)C=CC=1S(C)(=O)=O.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:44]=[C:43]([CH:45]([NH:47][C:48]2[CH:53]=[C:52](F)[CH:51]=[CH:50][C:49]=2[S:55]([CH3:58])(=[O:57])=[O:56])[CH3:46])[C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1.[NH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C)C=O.C(#N)C.O>[Cl:35][C:36]1[CH:44]=[C:43]([CH:45]([NH:47][C:48]2[CH:53]=[C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:51]=[CH:50][C:49]=2[S:55]([CH3:58])(=[O:57])=[O:56])[CH3:46])[C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1
Reactant: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc2c1OCO2
Reactant: C1CNCCN1
Agent: CC(N)c1cc(Cl)cc2c1OCO2
Agent: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O)c1cc(Cl)cc2c1OCO2
Temperature: 25 °C
Yield: 13.7 %

Procedure:
A solution of 1-(5-chlorobenzo[d][1,3]dioxol-7-yl)ethanamine (50.0 mg, 0.25 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (49.0 mg, 0.25 mmol) and diisopropylethylamine (129.0 mg, 4.0 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The crude extract which contained mainly N-(1-(5-chlorobenzo[d][1,3]dioxol-7-yl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine was used for the following reactions without further purification. A solution of N-(1-(5-chlorobenzo[d][1,3]dioxol-7-yl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (93.0 mg, 0.25 mmol), piperazine (432.0 mg, 5.0 mmol) and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) in acetonitrile (1 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo. The crude product was purified by silica chromatography (10% methanol in dichloromethane) to yield 15 mg (14%) of desired product. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 1H), 6.80 (d, 1H), 6.72 (s, 1H), 6.51 (d, 1H), 6.26 (dd, 1H), 5.99 (dd, 2H), 5.92 (s, 1H), 4.59 (m, 1H), 3.21 (m, 4H), 2.57 (m, 4H), 1.59 (d, 3H); MS (ESI) m/z: 438.3 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:44])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[C:33]([CH2:35][O:36]C3CCCCO3)[N:32]=[C:31]([CH3:43])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH2:35][C:33]1[CH:34]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:44])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:15])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:30]=[C:31]([CH3:43])[N:32]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M302) (0.46 g, 0.73 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (210 mg, 67%).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([F:19])=[CH:4][N:3]=1.[C:20]([O:24][C:25](=[O:27])[NH2:26])(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:20][O:24][C:25](=[O:27])[NH:26][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([F:19])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cnc(Br)c2sc(-c3c(Cl)cccc3Cl)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 70 °C
Yield: 124.3 %

Procedure:
A mixture of 4-bromo-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.60 g, 1.6 mmol), carbamic acid tert-butyl ester (0.936 g, 8.0 mmol), XantPhos (0.093 g, 0.16 mmol) and K3PO4 (0.678 g, 3.2 mmol), in toluene (10 mL) and water (2 mL), was degassed with a stream of argon. Pd2(dba)3 (0.073 g, 0.08 mmol) was added and the reaction mixture was heated at 70° C. for 3 hours in a sealed vial. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with EtOAc. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-40% EtOAc in pentane to afford the title compound as an off-white/yellow solid (0.74 g). LCMS (Method D): RT=4.26 min, m/z: 414 [M+H+].
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[C:21]([I:22])=[CH:20][C:13]([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:12][C:11]=2[I:23])=[CH:5][CH:4]=1.N[C@H:25](C(O)=O)CC1C=C(I)C(OC2C=C(I)C(O)=C(I)C=2)=C(I)C=1.C([O-])(O)=O.[Na+]>CO>[CH3:25][O:18][C:17](=[O:19])[C@H:15]([CH2:14][C:13]1[CH:12]=[C:11]([I:23])[C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[C:21]([I:22])[CH:20]=1)[NH2:16]
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Yield: 87 %

Procedure:
A 6 M solution of HCl in MeOH (8 mL; 4.8 mmol) was added to a suspension of O-(4-hydroxyphenyl)3,5-diiodo-L-tyrosine (2.12 g; 5 mmol) (prepared according to: Chalmers J. R., Dickson G. T., Elks J. and Hems D. A., “The Synthesis of Thyroxine and Related Substances”, Part V., J. Chem. Soc. (1949), 3424-3433) in MeOH (12 was stirred for 4 days at 20° C. Then a NaHCO3 saturated aqueous solution was added to the mixture until pH 7 was reached, obtaining a precipitate which was filtered by concentration of the solution a second crop of precipitate was obtained. The two samples were combined and dried (50° C.; 1.3 kPa) 3.7 mmol). Yield 87%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=1
Reactant: COC(=O)c1cc(NCCc2ccc(OC)cc2)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNc2cc(C(=O)O)nc(OC)n2)cc1
Reaction time: 5 h
Yield: 64 %

Procedure:
A mixture of 2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid methyl ester [650 mg, 2.02 mmol, Intermediate (55)] 5M sodium methoxide in MeOH (20 mL, 10.1 mmol), in MeOH (10 mL) is heated to reflux and stirred for 5 hours. The heating is turned off and the mixture is stirred for 15 hours at room temperature and concentrated by rotary evaporator to remove the solvent. The solid is dissolved in water and the solution is acidified to pH 2 with the addition of 1N hydrochloric acid. Extracted three times with 75 mL EtOAc and concentrated the combined organic extracts to afford 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid [390 mg, 64%, Intermediate (56)] as a solid. LCMS: RT=1.99 minutes, MS: 304 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>CN(C1C=CN=CC=1)C>[F:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1c(F)cccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: Cc1c(F)cccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 55 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 3-fluoro-2-methylbenzenesulfonyl chloride (210 mg, 1.04 mmol) and DMAP (cat.) gave the title compound (120 mg, 57%) after purification by column chromatography with DCM eluent.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[C:12]([N:8]1[C:9]2[C:4](=[C:3]([O:16][CH2:17][CH2:18][CH3:19])[C:2]([C:28]3[CH:29]=[N:30][N:31]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)[CH:32]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1c(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 100 °C
Yield: 82.9 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.050 g, 0.153 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.058 g, 0.153 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (0.012 g, 0.015 mmol), and cesium carbonate (0.150 g, 0.460 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 2.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (5)-tert-butyl 4-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.063 g, 83%) as an off-white solid. MS (ESI, pos. ion) m/z 497 [M+H]+