Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([O-:4])=[O:3].[N:12]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.ClC1C=CC=CC=1>O>[N+:2]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[NH:18])[CH:9]=[CH:10][CH:11]=1)([O-:4])=[O:3]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: N#CN1CCCC1
Agent: Cl
Solvent: O
Solvent: Clc1ccccc1
Product: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1

Procedure:
Samples of 3-nitroaniline hydrochloride, 15.5 g, and 1-pyrrolidinecarbonitrile, 9.6 g, were combined with 12 ml of chlorobenzene, and the mixture was warmed to reflux for three hours, and then allowed to cool. The resulting solid mass was taken up in 200 ml of hot water, and the chlorobenzene layer was separated. The aqueous layer was washed with 30 ml of chloroform and the combined organic layers were washed with 50 ml of water. The aqueous layers were combined, warmed, treated with charcoal and filtered hot. The filtrate was allowed to cool, and made strongly basic with 50% sodium hydroxide. This basic mixture was extracted with 200 ml of chloroform. The chloroform extract was concentrated on a steam bath to 150 ml, then diluted with hexanes to 300 ml, and stirred until yellow solids formed, giving 17 g of the N-(3-nitrophenyl)-1-pyrrolidinecarboximidamide. m.p. 117-118° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[O:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 88.2 %

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic phases were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C(O)(=[S:34])C.C(N(CC)CC)C>C(N(CC)CC)C.ClCCl>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[CH2:14][C:15]([SH:34])([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)=S
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-Methyl-4-[(E)-4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)-but-2-enoyl]-benzoic acid tert-butyl ester (1.29 g) was added thioacetic acid (6 eq.) and triethylamine (12 μL). The solution was stirred under argon at room temperature for 24 hours. More thioacetic acid (1 mL) and triethylamine (1 drop) were added and the solution was stirred under argon at room temperature for 72 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 2-Methyl-4-[4,4,4-trifluoro-3-mercapto-3-(3,4,5-trichloro-phenyl)-butyryl]-benzoic acid tert-butyl ester (573 mg).
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.CO[CH:48]1[CH:52]([CH2:53][C:54]([O:56][CH3:57])=[O:55])[CH2:51][CH:50](OC)O1.[F:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:57][O:56][C:54](=[O:55])[CH2:53][C:52]1[CH:51]=[CH:50][N:65]([C:64]2[CH:66]=[CH:67][C:61]([F:60])=[CH:62][CH:63]=2)[CH:48]=1
Reactant: COC(=O)CC1CC(OC)OC1OC
Reactant: Nc1ccc(F)cc1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Reaction time: 16 h
Yield: 80.9 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9-yl)-3(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, to a mixture of crude methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)-acetate (120 mg, ˜0.58 mmol) and 4-fluoroaniline (50 μL, 0.53 mmol) in 1,2-dichloroethane (10 mL) was added trifluoroacetic acid (0.2 mL, 0.26 mmol). After 16 hours at 80° C., the resultant mixture was partitioned between EtOAc and 1M pH 7 phosphate buffer. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to a crude oil, which was purified via flash column chromatography with 0-15% EtOAc/hex gradient eluant to yield 100 mg (77%) of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an oil. 1H NMR: δ 7.34-7.30 (m, 2H), 7.10 (t, 2H, J=8.6 Hz), 6.96-6.94 (m, 2H), 6.28 (t, 1H, J=2.2 Hz), 3.72 (s, 3H), 3.56 (s, 2H). Anal. Calculated for C13H12NO2F•0.6 H2O: C, 63.98; H, 5.45; N, 5.74. Found: C, 64.01; H, 5.04; N, 5.65.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:11]1([C:17]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[C:19]([C:17]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:18])[CH:20]=[CH:21][CH:22]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1cccc(-c2cnc3[nH]ccc3c2)c1)N1CCOCC1
Temperature: 110 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (3 g, 15 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (4 g, 18 mmol), sodium bicarbonate (4 g, 46 mmol), and tetrakis(triphenylphosphine)palladium(0) in dioxane/water (100 mL/20 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (3.86 g, 84% yield) as yellow solids. MS: m/z 308.1 (M+H+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]([Cl:13])=[O:10]
Reactant: O=C(O)c1ncccn1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ncccn1
Temperature: 25 °C
Yield: 67 %

Procedure:
A stirred mixture of 0.837 g of 2-pyrimidinecarboxylic acid hydrochloride (prepared as described in S. Gronowitz et al. Ark. Chem, 1964, 22, 66-82), 30 mL of CHCl3 and 2 mL of thionyl chloride was heated at reflux for 12 h. After cooling to r.t., the suspension was filtered and the filtrate was evaporated to dryness in vacuo to afford 0.306 g (67%) of the title compound as a green solid used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>ClCCl>[F:10][C:8]([F:11])([F:9])[C:6]1[C:5]([Cl:12])=[CH:4][C:3]2[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:28](=[O:30])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-trifluoromethylphenyl)amino]-1-piperidinecarboxylate (D62, 2.2 g) was dissolved in 25 ml of dichloromethane at 0° C. and triphosgene (0.6 g) and diisopropylethylamine (1.0 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, then crystallised from diethyl ether to yield the subtitle compound, 1.0 g.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])=O.[Na+].[Br:27]Br.O>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 72 h
Yield: 29.8 %

Procedure:
A solution of the compound of Example 1, Step 3 (525 mg, 1.85 mmol) in HOAc (20 mL) at room temperature was treated with NaOAc (182 mg, 2.22 mmol) followed by Br2 (296 mg, 1.85 mmol). The mixture was stirred at 55° C. for 72 h then cooled and poured into water. The resulting precipitate was collected and air dried to afford the desired product as a white solid (200 mg, 30%); 1H NMR (DMSO-d6) δ 7.35 (m, 5H), 5.71 (d, J=16.5 Hz, 1H), 5.21 (d, J=16.5 Hz, 1H), 5.16 (t, J=7.5 Hz, 1H), 2.51 (s, 3H), 2.49 (m, 1H), 2.28 (m, 1H), 0.78 (t, J=7.5 Hz, 3H); LC/MS (ESI): 284 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][CH2:11][CH3:12])=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH3:12])=[C:4]([NH:9][C:28](=[O:29])[CH2:27][C:25]#[N:26])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNc1c(Br)cnc(Cl)c1N
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCNc1c(Br)cnc(Cl)c1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 5-bromo-2-chloro-N4-ethyl-pyridine-3,4-diamine (II, 550 g, 2.21 mol) in CH2Cl2 (5.5 L) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (634.5 g, 3.31 mol), cyanoacetic acid (282 g, 3.31 mol) and N-methylmorpholine (897 g, 8.84 mol). A significant exotherm (˜20° C.) was observed upon the addition of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and cyanoacetic acid. After stirring at ambient temperature for 2 h, the solvent was removed under reduced pressure. The resulting reside was extracted with warm EtOAc (40° C., 20 L) and water (40° C., 8 L). The aqueous layer was washed with addition EtOAc (10 L) and the combined organic extracts were washed with water (10 L). The organic extract was concentrated under reduced pressure to a slurry and filtered. The solid was washed with EtOAc and dried to give 534 g (76% yield) of the desired compound (III) as a white crystalline solid. This was used in the next step without further purification. MS (ES+) m/z 317 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[C:28]1([C:34]2[CH:35]=[CH:36][C:37]([CH2:40]Br)=[N:38][CH:39]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:40][C:37]4[CH:36]=[CH:35][C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:39][N:38]=4)=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3ccc(-c4ccccc4)cn3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (180 mg) (Preparation 1), 5-phenyl-2-picolyl bromide (138 mg), K2CO3 (84 mg) and Cs2CO3 (30 mg) in DMF (5 mL) wase stirred at r.t. under nitrogen for 48 hours. The mixture was poured onto 1N HCL, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated to dryness. The residue was purified by column chromatography (hexane/EtOAc 5:1 then 1:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27].ClCCl>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:27]#[C:26][CH2:25][OH:28])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(C#CCO)c21

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)palladium(II) chloride (0.012 g), and propargyl alcohol (0.035 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Dichloromethane followed by hexanes is added to the reaction mixture. The resulting solid is filtered, washed thoroughly with hexanes, and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 0.5% MeOH:CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L), 1.5% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (1 L), 3% MeOH:CH2Cl2 (1 L)) affords the title compound as a yellow solid (0.13 g).
Reaction SMILES: C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[C:32]([O:34][CH3:35])=[O:33].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][CH3:49])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][CH3:49])[C:45]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@H:24]1[C:32]([O:34][CH3:35])=[O:33])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (3.15 ml) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (5.75 g, 22.6 mmol) were added to a solution of methyl indoline-2-carboxylate (2 g, 11.3 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (2.6 g, 13.6 mmol) in methylene chloride (15 ml), at 0° C. under nitrogen. The reaction was stirred for 2 h at 5° C. and then at room temperature overnight. The mixture was filtered, the filtrate was washed with water (2×40 ml) and the combined aqueous fractions were extracted with methylene chloride. The combined organic fractions were dried and concentrated to give a residue, which was purified by chromatography on a column of silica gel, using a 7/3 petroleum ether/ethyl acetate mixture as eluent. The product was obtained in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[C:31]([O:32][CH3:33])[CH:30]=1)=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (8.20 g, 0.026 mol, 1.0 equivalent) in anhydrous THF was cooled to 0° C. in an ice bath under N2. A chilled 0.5M solution of 3,4-dimethoxyphenylmagnesium bromide in THF (52.1 mL, 0.026 mol, 1.0 equivalent) was slowly added. The reaction mixture was allowed to stir for two hours. The reaction was quenched upon addition of saturated NH4Cl solution (10 ml). The mixture was partitioned between ethyl acetate and brine. The organic extract was washed with brine (3×100 ml). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude blue oil was filtered through a layer of silica. The filtrate was concentrated in vacuo to afford 2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acid benzyl ester (10.46 g, 0.023 mol, 88% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.5-7.3 (6H, m), 7.0-6.7 (2H, m), 5.2 (2H, m), 4.0-3.8 (6H, m), 3.0 (1H, m), 2.6-1.9 (4H, m), 1.4 (9H, s). MS (LC-MS): Calculated for C25H31NO7 457.21, found 458.19 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH2:28].ClCCl>CCCCCC>[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH:28][C:10](=[O:12])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH3:13]
Reactant: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-3-nitro-phenyl)-propionic acid (0.60 g, 2.70 mmol), SOC2 (0.96 mL, 13.0 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (0.77 g, 3.50 mmol). After normal workup, the pure objective compound (0.98 g, 82%) was obtained as white solid by recrystallization (dichloromethane:n-hexane=1:3): m.p 122° C.; 1H NMR (200 MHz, CDCl3) δ 1.60 (d, J=7.2 Hz, 3H, CH3), 3.65-3.84 (m, 4H, CO2CH3 & CH), 7.55 (dd, J=8.8, 2.2 Hz, 1H, ArH), 7.84 (d, J=2.2 Hz, 1H, ArH), 8.44 (d, J=2.0 Hz, 1H, ArH), 9.51 (br s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]([CH3:26])[N:14]=1>>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:26])[N:14]=[C:13]2[NH:12][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cn1nc(N)c2cc(C(F)(F)F)ccc21
Reactant: COC(=O)c1ccncc1Br
Product: Cn1nc(Nc2cnccc2C(=O)O)c2cc(C(F)(F)F)ccc21
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield from methyl 3-bromoisonicotinate and 3-amino-5-trifluoromethyl-1-methyl-indazole according to the general procedure for Example 6. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (3H, s), 7.72-7.83 (3H, m), 7.99 (1H, s), 8.21 (1H, d, J=5.0 Hz), 9.64 (1H, s), 10.69 (1H, br s), 14.12 (1H, br s). [M+H] calc'd for C15H11F3N4O2, 337; found 337.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>COCCOC>[CH2:13]([O:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OCC(CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OCC(COCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 5-hydroxymethyl-2,2-dimethyl-1,3-dioxane (cf:Bates, H. A.; Farina, J.; Tong, M. J. Org. Chem. 1986, 51, 2637, 3.0 g, 20.5 mmol) in 25 mL of dry DME under argon was added via cannula to a slurry of NaH (0.740 g, 80% dispersion in oil, 24.6 mmol) in 60 mL of dry DME cooled to 0° C. The resulting grey slurry was stirred at room temperature for 0.5 h, then recooled to 0° C., and treated with a solution of benzylbromide (4.56 g, 26.7 mmol) in 20 mL of DME. The reaction mixture was stirred at room temperature (rt) overnight and then quenched with 100 ml of H2O. The aqueous layer was separated and extracted with two portions of ethyl acetate. The combined organic layers were then washed with saturated sodium chloride solution, dried over MgSO4, filtered, and concentrated to provide a yellow oil. Purification by column chromatography on silica gel (ethyl acetate/hexane) afforded 3.51 g (72%) of 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane as a clear colorless liquid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1)[OH:4].[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.O1CCOCC1>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:2]([F:1])([F:19])[F:20])[N:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: N#Cc1ccc(-c2ccccc2C(O)C(F)(F)F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccccc3-c3ccc(C#N)nc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 110 °C
Yield: 84 %

Procedure:
A mixture of 5-[2-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-pyridine-2-carbonitrile (46 mg, 0.165 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (59 mg, 0.15 mmol), cesium carbonate (195 mg, 0.6 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature, then was poured into 5 ml of water. 1N HCl was added to adjust pH to 4.5, the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated to give 80 mg of crude (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid, yield 84%.