Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17].C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Temperature: 25 °C
Yield: 78 %

Procedure:
Piperidine (0.50 mL, 5.1 mmol) was added to a suspension of 4-hydroxy-3-methoxybenzaldehyde (0.77 g, 5.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.0 g, 4.5 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (12.0 mL) and water (12.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.1 g, 78%) as a yellow crystalline solid; mp 207.5-208.5° C., lit.5 230-233° C.; δH (500 MHz, DMSO-d6) 3.83 (s, 3H, OCH3), 6.71 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6=8.5 Hz, 1H, H5′), 7.13 (dd, J5,6=8.5, J2′,6′=1.5 Hz, 1H, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.34 (d, J2′,6′=1.5 Hz, 1H, H2′), 7.52 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=2.0 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=2.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 9.57 (s, 1H, OH), 11.27 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [CH3:1][N:2]([C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19]Br)=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].C[Sn](C)(C)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][N:2]([C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7]
Reactant: C[Sn](C)(C)c1cccnc1
Reactant: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(C#CBr)cc1-c1ccccc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(C#Cc2cccnc2)cc1-c1ccccc1C
Yield: 25.3 %

Procedure:
Methyl N-[4-(bromoethyn-1-yl)-2-(2-methylphenyl)benzoyl]methionine (200 mg, 0.43 mmol), trimethyl-3-pyridyltin (89 mg, 0.37 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (15 mg, 0.02 mmol) were heated at 80° C. for 18 h. The mixture was evaporated and chromatographed (50% ethyl acetate in hexane) to give 43 mg of the title compound. MS m/e 459 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.60 (m, 1H), 1.86 (m, 1H), 2.1 (m, 8H), 3.68 (s, 3H), 4.63 (m, 1H), 5.97 (m, 1H), 7.30 (m, 6H), 7.63 (m, 1H), 7.83 (m, 1H), 7.99 (m, 1H), 8.59 (m, 1H), 8.78 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=3)[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23][CH2:34][CH2:35][CH2:36][N:13]2[CH2:14][CH2:19][CH2:20][CH2:12]2)[CH:15]=3)[CH:7]=1)[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(O)cc3n2CC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(OCCCN4CCCC4)cc3n2CC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a solution of [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2CO3 (538 mg, 3.9 mmol) and 3-bromo-1-chloropropane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 50° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:10][OH:11]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5](=[N:10][OH:11])[NH2:6]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: NO
Solvent: CO
Product: NC(=NO)c1ccnc(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 2-chloroisonicotinonitrile (Aldrich, 0.73 g, 5.27 mmol), and hydroxylamine (Aldrich, 50 wt %, 0.348 g, 5.27 mmol) in methanol (10 mL) was heated to reflux and stirred for 1 hour. The volatiles were removed under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.09 (s, 2H), 7.67 (dd, J=5.4, 1.4 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 8.40 (d, J=5.2 Hz, 1H), 10.22 (s, 1H) ppm; MS (DCl/NH3) m/z 172 (M+H)+, 174 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CCl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CN3C(=O)CCC3=O)cc2)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of [5-({[1-(4-Chloromethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (67 mg, 0.1 mmol), succinimide (12 mg, 0.1 mmol) and potassium carbonate (84 mg, 0.6 mmol) in 50 mL acetone was stirred at 80° C. for 24 h. The mixture was filtrated and concentrated in vacuo. The crude was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min) to yield the title compound. LCMS (method A) RtA=1.339 min; [M+H]+=547.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[CH2:23][N:21]1[N:20]=[N:19][C:18]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[N:22]1
Reactant: NNC(=O)Cn1nnc(N2CCCC2)n1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(Cn1nnc(N2CCCC2)n1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[5-(1-pyrrolidinyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 67 mg of the title compound (72%) as a yellow powder in 95% purity by HPLC (Rt: 4.24, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([N:20]([CH3:19])[CH3:30])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(N(C)C)c3)CC2)ccc1Cl
Yield: 33 %

Procedure:
The title compound (14 mg, 33%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-dimethylaminobenzoic acid. MS: 416.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([C:14]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH2:35][C:36]([F:38])([F:39])[F:37])[CH2:26][CH2:27]2)=[O:16])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Yield: 75 %

Procedure:
The title compound was synthesised according to the procedure described in Example 1 but using 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylic acid instead of 3-phenyl-5-methyliso-xazole-4-carboxylic acid and Compound 12B instead of Compound 1B. Extraction with diethyl ether followed by purification by flash chromatography (chloroform-2 N ammonia in methanol 100:3) afforded the title compound (75%) as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][CH:7]([OH:8])[C@@H:6]1[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(=[O:3])[CH3:2].[Cl:32][C:33]([Cl:37])([Cl:36])[C:34]#[N:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:32][C:33]([Cl:37])([Cl:36])[C:34](=[NH:35])[O:8][C@@H:7]1[O:9][C@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(=N)C(Cl)(Cl)Cl)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 36 (4.0 g, 6.98 mmol) and trichloroacetonitril (4.2 ml, 14.88 mmol) in CH2Cl2 (25 ml) 18 g of finely powdered dry K2CO3 are added. After stirring for 60 min at RT the mixture is filtered through Celite®. Chromatography (silica gel, 500 g, hexane/ethyl acetate=2:1) gives 37 (β-anomer).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+]>C(O)C.C1C=CC=CC=1>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccccc1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1
Reaction time: 12 h

Procedure:
2-Amino-2-phenyl-acetonitrile (0.04 mole) and benzoyl acetone (0.04 mole) are refluxed for four hours in 30 ml. of anhydrous benzene in the presence of 100 mg. of p-toluenesulfonic acid. After cooling the reaction mixture is filtered and the solvent is evaporated off to give an oily residue which is dissolved in an ethanol solution containing sodium ethoxide (0.041 mole) and the mixture is allowed to stand for 12 hours at the room temperature. The solid precipitate which forms is recovered by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Cl:1][C:2]1[C:3](/[C:4](/[OH:6])=[CH:26]\[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:19])[N:25]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18]
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1Cl
Product: C=CCOC(=O)Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl
Yield: 79.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step B using methyl 2-chloro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (30 g, 0.11 mol) and 2-chloro-4-methylpyrimidine (15.8 g, 0.12 mol) the title compound of Step B was prepared (29 g, 79.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.52-13.58 (br, 0.9H), 8.41-8.42 (m, 1H), 8.22-8.27 (m, 1H), 7.28-7.35 (m, 2.2H), 7.21-7.24 (m, 1.2H), 6.85-6.88 (m, 1H), 5.91-6.02 (m, 1H), 5.73 (s, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14](O)=[O:15])=[C:9]2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([Cl:31])=[O:15])=[C:9]2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Cl)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 1.5 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (1.5 g, 5.3 mmol) in acetone (150 mL) was added a 0.3 M solution of KMnO4 (150 mL). The reaction mixture was stirred 3 h at room temperature and then was charged with 10% H2O2 (5 mL). After 15 minutes the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove acetone. The remaining aqueous suspension was acidified with acetic acid. The precipitates were recovered by filtration and dried under high vacuum to afford 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.99 g, 62%) as a faintly yellow powder; 1H NMR (CDCl3): δ 7.56 (dd, J=8, 3 Hz, 1H), 7.41 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.42 (s, 1H), 2.21 (s, 3H), 1.90 (s, 3H); MS (ESI) m/z 302 [M+H]+. To a suspension of 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.65 g, 2.16 mmol) in anhyd toluene (5.0 mL) cooled to 0-3° C. were added thionyl chloride (0.25 mL) and DMF (20 μL). The reaction mixture was allowed to warm to room temperature where it remained for 3 h and then was concentrated in vacuo. The residue was evaporated twice from 5 mL of toluene to remove thionyl chloride and then was triturated in 3 mL of hexanes. The solids were removed by filtration and the filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound (0.44 g, 64%) as a pale brown solid; 1H NMR (CDCl3): δ 7.59 (dd, J=8, 3 Hz, 1H), 7.44 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.51 (s, 1H), 2.17 (s, 3H), 1.89 (s, 3H); MS (ESI) m/z 320 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1)=[O:26]
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](N)CCO2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@@H](O)[C@H](NC(=O)CCl)CCO2
Reaction time: 24 h
Yield: 81 %

Procedure:
A solution of 17 g of trans-4-amino-7-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-ol dissolved in 700 ml of hydrocarbon-stabilized chloroform was treated with 16 ml of triethylamine at room temperature and 10 g of chloroacetyl chloride dissolved in 80 ml of chloroform was slowly added thereto. The reaction mixture was allowed to stand at room temperature for 24 hours and the solid removed by filtration and washed with chloroform. The filtrate was washed twice with dilute hydrochloric acid solution, followed by a wash with water and dried over anhydrous magnesium sulfate. The filtrate was evaporated to dryness and triturated with ether to yield 18.8 g of trans-2-chloro-N-(2,3,4,5-tetrahydro-5-hydroxy-7-methoxy-1-benzoxepin-4-yl)acetamide.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[CH:22]=[CH:23][O:24][CH2:25][CH3:26])CCC>C(OCC)(=O)C.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>[Cl:8][C:5]1[N:4]=[C:3]([NH2:9])[C:2]([CH:22]=[CH:23][O:24][CH2:25][CH3:26])=[CH:7][N:6]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC=Cc1cnc(Cl)nc1N
Temperature: 110 °C
Reaction time: 15 h
Yield: 45.9 %

Procedure:
A 500 mL round bottomed flask is charged with 5-bromo-2-chloropyrimidin-4-ylamine (1) (10 g, 48 mmol), tetrakis(triphenylphosphine)palladium(0) (2.8g, 2.5 mmol), and toluene (200 mL). Tributyl-(2-ethoxyvinyl)-stannane (22 g, 60 mmol) is added and the reaction heated to 110° C. with stirring for approximately 15 hours. After cooling to room temperature, the solution is diluted with 100 mL ethyl acetate and washed with water and brine. The organic extract is dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, Hexane:Ethyl acetate/5:1) provides 2 (4.4 g, 46%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([C:22](=[O:23])[CH2:21][N:17]3[CH2:18][CH2:19][CH:14]([C:12]([C:10]4[S:11][C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=4)=[O:13])[CH2:15][CH2:16]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: O=C(CCl)c1ccc2c(c1)OCCO2
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)OCCO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (333 mg, 1.2 mmol) and 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (256 mg, 1.2 mmol) in DMF (4 ml) was treated with DIPEA (199 ul, 1.2 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Chromatography on SiO2 (hex/EtOAc 1:1, EtOAc) and crystallisation from ether gave 350 mg (65%) of title compound as a yellowish solid.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[Cl:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: COc1ccc(C#N)cc1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-chloro-4-methoxybenzonitrile (0.757 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 84% yield) as a solid after drying. MS: MS m/z 316.1 (M++1).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@H:17]([O:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[C:27]([CH3:37])=[C:26]2[CH3:38])=[CH:22][CH:21]=1)[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:39]=[CH:40][C:20]([O:19][C@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])=[CH:21][CH:22]=2)[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Cl[CH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[O:28][N:27]=1>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: Cc1cc(CCl)no1
Product: Cc1cc(COc2c(Br)cc(CC(N)C(=O)O)cc2Br)no1
Yield: 22 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 3-chloromethyl-5-methylisoxazole and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 22% yield of 2-amino-3-[3,5-dibromo-4-(5-methylisoxazol-3-ylmethoxy)phenyl]propionic acid. LC/MS (electrospray): m/z 433 (M−1).