Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:28])[C:18]=2[CH3:29])=[CH:7][CH:6]=1)(=O)C>Cl.CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:28])[C:18]=2[CH3:29])=[CH:9][CH:10]=1
Reactant: COC1=C(OC)C(=O)C(CCCCCCc2ccc(OC(C)=O)cc2)=C(C)C1=O
Agent: Cl
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCc2ccc(O)cc2)=C(C)C1=O
Reaction time: 4 h
Yield: 44.2 %

Procedure:
6-[6-(4-Acetoxyphenyl)hexyl]-2,3-dimethoxy-5-methyl-1,4-benzoquinone (2.1 g) is dissolved in a mixture of concentrated hydrochloric acid (0.3 ml) and methanol (55 ml), and the solution is allowed to stand at room temperature for 4 hours. The methanol is distilled off under reduced pressure, and the residue is diluted with water and extracted with ethyl acetate (200 ml). The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography. The fractions containing the desired product are recrystallized from ether-hexane to give 830 mg of 6-[6-(4-hydroxyphenyl)hexyl]-2,3-dimethoxy-5-methyl-1,4-benzoquinone, m.p. 87°-88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])(=[O:22])[CH3:21]
Reactant: Cc1ccc2ccccc2c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C)ccc2ccccc12
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of 9.48 g (60 mmole) of 2-methyl-1-naphthol and 8.10 g (80 mmole) of triethylamine in 50 mL of ethyl acetate was cooled to below 5° C. in an ice-bath. 5.50 g (70 mmole) of acetyl chloride was added at a rate such that the temperature did not rise about 5° C. The reaction mixture was stirred for an additional one hour, diluted with 50 mL of ethyl acetate, and washed with water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily residue. Crystallization in hexane yielded 7.58 g (63% yield) of the title compound with a melting point of 81°-83° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ2.26 (s, 3H), 2.48 (s, 3H), 7.42 (d, 1H, J=9 Hz), 7.46-7.55 (m, 2H), 7.47-7.81 (m, 2H), 7.92 (d, 1H, J=9 Hz). The mass spectrum showed a molecular ion at m/z 200.
Reaction SMILES: [NH2:1][C:2]1([C:16]#[N:17])[CH2:15][CH2:14][C@H:13]2[C@@H:4]([CH2:5][C:6]3[C:11]([CH2:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH2:17][CH2:16][C:2]1([NH2:1])[CH2:15][CH2:14][C@H:13]2[C@@H:4]([CH2:5][C:6]3[C:11]([CH2:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3]1
Reactant: N#CC1(N)CC[C@@H]2Cc3ccccc3C[C@H]2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(N)CC[C@@H]2Cc3ccccc3C[C@H]2C1
Reaction time: 1 h

Procedure:
A solution of 1.39 g (6.1 mmol) of the nitrile obtained in Step 5 in 35 ml of THF is added dropwise to a suspension of LiAlH4 (350 mg, 9.2 mmol) in 35 ml of anhydrous THF at −20° C. under nitrogen. The mixture is stirred for 1 hour 30 before being hydrolysed with 2.3 ml of H2O, 4.6 ml of 35% sodium hydroxide solution and 4.9 ml of water. The resulting suspension is filtered and the filtrate is evaporated to yield an oil which is subjected to flash chromatography over a column: the title compound is isolated in the form of a mixture of two diastereoisomers which are separable by HPLC (Kromasil 100, 10 C18-210 mm—CH3CN/H2O/CF3COOH=170/830/5).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.[O:27]1[C@@H:29]([CH2:30][CH3:31])[CH2:28]1>>[OH:27][C@@H:29]([CH2:30][CH3:31])[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[CH:15][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]3)=[CH:17][CH:18]=1)[CH2:6][CH2:5]2
Reactant: CC[C@H]1CO1
Reactant: CN1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2)CC1
Product: CC[C@H](O)COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C)CC3)cc1)C2=O

Procedure:
6-Hydroxy-2-[4-(4-methyl-[1,4]diazepan-1-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one and (S)-(−)-1,2-epoxybutane were reacted according to Method T1. In this way the product was obtained with molecular weight 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[C:27]#[N:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:27]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH3:26])=[O:24])#[N:28]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reaction time: 2 h
Yield: 69.5 %

Procedure:
Methyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate (400 mg, 0.977 mmol) was diluted with CH2Cl2 followed by the addition of TFA (1 mL). After stirring for 2 hours, the reaction was concentrated to yield the title compound (240 mg, 69.5% yield).
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@H:7]([CH2:13][P:14](/[CH:18]=[CH:19]/[C:20]1[C:21]([CH:39]([CH3:41])[CH3:40])=[N:22][C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)([O:16][CH3:17])=[O:15])[CH2:8][C:9]([O:11][CH3:12])=[O:10])(C)C.CC(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]2[CH:24]=[C:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:22]=[C:21]([CH:39]([CH3:40])[CH3:41])[C:20]=2/[CH:19]=[CH:18]/[P:14]([O:16][CH3:17])([CH2:13][C@@H:7]([OH:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:15])=[CH:27][CH:28]=1
Reactant: COC(=O)C[C@@H](CP(=O)(/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CP(=O)(/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C)OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.3 %

Procedure:
A solution of (S,E)-3-[[(1,1-Dimethylethyl)-diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoic acid, methyl ester (826 mg, 1.10 mmol) in THF (10 ml) was treated with HOAc (320 ul, 336 mg, 5.6 mmol) and tetra-n-butylammonium fluoride (1.0M in THF, 3.3 ml, 3.3 mmol). After stirring at room temperature for 22 hours, the solution was poured into saturated NaHCO3 and extracted with EtOAc. The EtOAc extract was washed with brine, dried (Na2 SO4), filtered, and stripped to give an oil which was subsequently chromatographed (flash, Merck SiO2, 30% acetone in hexane followed by 50% acetone in hexane). (S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (497 mg, 88%) was obtained as a white oily foam.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]1[CH:60]=[CH:59][N:58]=[CH:57][C:56]=1[C:61](Cl)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][N:55]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(Cl)c1cnccn1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnccn2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 46 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and pyrazine-2-carbonyl chloride as starting materials in 46% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.80 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.32 (d, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.04 (d, 1H), 4.52 (d, 1H), 3.62 (d, 1H), 3.12 (m, 1H), 2.98 (m, 4H), 2.88 (m, 1H), 2.34 (m, 2H), 2.12 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.25 (m, 2H). LCMS for C29H29ClN9O2 (M+H)+: m/z=570.2.
Reaction SMILES: [P:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6]1)=[O:2].[O:27]=[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][C:36]([Sn](C)(C)C)=[CH:35][CH:34]=2)[CH2:31][C@H:30]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:29]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1>[P:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:36]3[CH:35]=[CH:34][C:33]([N:32]4[CH2:31][C@H:30]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:29][C:28]4=[O:27])=[CH:38][CH:37]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCC1CC(c2ccc(Br)cc2)=NO1)OC(C)(C)C
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(COP(=O)(OC(C)(C)C)OC(C)(C)C)C4)cc3)cc2)C(=O)O1
Temperature: 90 °C
Reaction time: 5 h
Yield: 36.3 %

Procedure:
[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methyl di-tert-butyl phosphate (0.25 g, 0.55 mmol), N-({(5S)-2-oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (0.25 g, 0.66 mmol), tri-2-furylphosphine (0.026 g, 0.11 mmol) and tris(dibenzylideneacetone)palladium (0) (0.05 g, 0.55 mmol) were dissolved in 1,4-dioxane (5 ml) and degassed three times. The mixture was heated to 90° C. and stirred for 5 hr, then stirred at 25° C. for 12 hours. The solution was concentrated in vacuo and purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.12 g of the desired product as a yellowish white foam.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2c(F)cccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.399 g, 1.04 mmol) (from example 127, step 1) was dissolved in MeOH (3.5 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.306 mL, 1.04 mmol) was added over 5 min. After 45 min with stirring, hydroxylamine (50% by weight in water, 0.064 mL, 1.04 mmol) was added over one minute and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5.36 mL, 32.16 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated to give crude trans-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.331 g, 90%). MS m/z 353 (M+H)+
Reaction SMILES: [CH2:1]1[C:9]2[C:5](=[CH:6][C:7]([P:20]([O:26]C(C)C)(=[O:25])[O:21]C(C)C)([P:10]([O:16]C(C)C)(=[O:15])[O:11]C(C)C)[CH:8]=2)[CH:4]=[CH:3][NH:2]1.ClCC1C=NC=CC=1CCl>>[CH2:1]1[C:9]2[C:5](=[CH:6][C:7]([P:10]([OH:15])(=[O:11])[OH:16])([P:20]([OH:26])(=[O:21])[OH:25])[CH:8]=2)[CH:4]=[CH:3][NH:2]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)C=C2C=CNCC2=C1
Agent: ClCc1ccncc1CCl
Product: O=P(O)(O)C1(P(=O)(O)O)C=C2C=CNCC2=C1

Procedure:
Using essentially the same procedure as in Example 1(a), tetraisopropyl methylene diphosphonate is converted to tetraisopropyl dihydro-2-pyrindine-6,6-diphosphonate by reaction with 3,4-bis(chloromethyl)pyridine. The resulting ester is hydrolyzed as in Example 1(a) to yield dihydro-2-pyrindine-6,6-diphosphonic acid. The dihydro-2-pyrindine-6,6-diphosphonic acid is then converted to the octahydro-2-pyrindine-6,6-diphosphonic acid by a hydrogenation procedure which is essentially the same as in Example 1(b). Substituted octahydro-2-pyrindine-6,6-diphosphonic acid compounds are prepared as described hereinbefore, in Example 1, by using as the starting material the appropriately substituted 3,4-bis(chloromethyl)pyridine.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])[CH:4]=[CH2:5].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:6]1([CH2:3][CH:4]=[CH2:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: C=CCC1C(=O)CCc2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
Into a flame-dry 500 ml 3-neck flask provided with mechanical stirrer, dropping funnel and a nitrogen inlet tube was placed 4.21 g sodium hydride (55% dispersion in oil, 100 mmol) with the apparatus placed under nitrogen. The oil was washed out with benzene (3×30 ml), 40 ml dry dimethylformamide was added and the suspension was stirred and cooled in an ice-bath. A solution of 21.6 g (100 mmol) 1-allyl-3,4-dihydro-7-methoxy-2(1H)naphthalenone (VIIIa) in 10 ml dimethylformamide was added dropwise (10 min), then the cooling bath was removed and stirring at room temperature continued until the evolution of gas ceased (2 hr). The brown-colored reaction mixture was cooled (ice-bath) and a solution of 16.7 g (100 mmol) ethyl bromoacetate in 40 ml dimethylformamide was added dropwise keeping the reaction temperature below 25° C. After the addition (15-20 min) stirring in cold was continued for 1 hr and then overnight at room temperature. Water (300 ml) was added and extracted with ether (3×100 ml). The combined ether extracts were washed with water (2×100 ml) dried (MgSO4), the solvent removed by evaporation and the residue was distilled to give 26.0 g (86%) IXa, b.p. 145°-150°/0.05-0.01 mm Hg; IR (neat) 1740, 1715 cm-1 ; NMR δ, 1.05 and 3.92 (triplet and quartet for OCH2CH3), 3.75 (s, 3, OCH3), 4.65-6.0 (m, 3, CH=CH2), 6.55-7.15 (m, 3, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48](OS(C(F)(F)F)(=O)=O)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][CH:65]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([C:62]5[CH:63]=[CH:64][CH:65]=[C:60]([Cl:59])[CH:61]=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OS(=O)(=O)C(F)(F)F)cc1)CO3
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: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Temperature: 90 °C
Yield: 54.5 %

Procedure:
To a solution of (3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(4-trifluoromethanesulfonyloxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (0.075 g) in toluene (4.0 mL) was added 3-chlorophenylboronic acid (0.0337 g), Pd(PPh3)4 (0.0052 g), and Na2CO3 (24 mg in 1.0 mL H2O). The mixture was heated at 90° C. for 3.0 hours. After completion of the reaction, the aqueous layer was drained. The organic layer was poured on to a silica gel column chromatography and eluted with 1% MeOH, 1:1 hexanes/EtOAc to provide (3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (0.039 g) which was deprotected according to General Procedure C to provide (S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.025 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:18][CH:19]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (500 mg), N-(4-aminophenyl)morpholine (385 mg), EDAC (828 mg), HOBT (583 mg) and N-methylmorpholine (714 μl) in DMF (5 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (818 mg)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]=1[CH3:21])=[O:13])[CH3:10].O>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[C:18]([I:1])[C:17](=[O:20])[NH:16][C:15]=1[CH3:21])=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(I)c(=O)[nH]c1C
Temperature: 95 °C

Procedure:
N-Iodosuccinimide (40 g, 180 mmol) was added to a suspension of intermediate (5b), 2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (18.1 g, 100 mmol) in acetonitrile (400 mL), under a nitrogen atmosphere. The resulting suspension was heated at 95° C. for 5 hours to give an initial orange solution. An off-white precipitate slowly formed. The resulting suspension was allowed to cool and was poured into water (1200 mL) to give an off-white precipitate. The separated by filtration and the solids washed with water (500 mL) to give an off-white powder. The solids were dried in vacuo (60° C.) to give the product as an off-white powder, 28.3 g (92%)
Reaction SMILES: CS(C)=O.C(=O)=O.CC(C)=O.C(Cl)(=O)C(Cl)=O.[C:18]([O:22][C:23](=[O:37])[NH:24][CH2:25][CH:26]([OH:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl.O>[C:18]([O:22][C:23](=[O:37])[NH:24][CH2:25][C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of dimethyl sulfoxide (25.2 ml, 0.36 mol) in methylene chloride (357 ml) at −78° C. (dry ice/acetone) was added a solution of oxalyl chloride (20 ml, 0.23 mol) in methylene chloride (115 ml). The reaction mixture was stirred at −78° C. for 30 min under an atmosphere of N2 then a solution of (3-tert-Butoxycarbonylamino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (31.9 g, 0.11 mol) in methylene chloride (300 ml) and triethylamine (75 ml, 0.54 mol) were added. The reaction was stirred for 16 hours, allowing the reaction to warm up to room temperature. The mixture was diluted with water (800 ml) and extracted with methylene chloride (2×300 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellowish oil. Purification via column chromatography on silica gel (ethyl acetate:hexane, 3:7, v/v) afforded the product as a white solid (28 g, 88%). 1H NMR (CDCl3) δ 1.44 (s, 18H), 4.04 (m, 4H), 5.19 (s, 1H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C=Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=413.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 1-fluoro-3-isocyanato-benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[C:12](=[CH:7][N:10]([CH3:15])[CH3:11])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N2CCC(=O)CC2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCC(=O)C(=CN(C)C)C2)cc1

Procedure:
A solution of methyl-4-(4-oxopiperidin-1-yl)-benzoate (4.06 g, 17.40 mmol) and DMF-dimethylacetal (9.32 mL, 69.61 mmol) in 1,4-dioxane (100 mL) was refluxed for 40 hours. The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 5% MeOH in EtOAc to 8% MeOH in EtOAc) to obtain the title compound as an orange, crystalline solid (3.00 g, 60%).