Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[CH:18]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].[CH3:36][S:37](Cl)(=[O:39])=[O:38].Cl.[NH2:42]O.[O-]CC.[Na+]>ClCCl.C(O)C.C(N(CC)CC)C>[CH2:9]([O:8][C:6]1[C:5]([O:16][CH3:17])=[CH:4][C:3]([CH:18]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH2:42])=[NH:35])=[CH:32][CH:33]=2)[CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])=[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OC)c(OCc2ccccc2)cc1N
Reactant: CS(=O)(=O)Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCC(Nc1ccc(C(=N)N)cc1)c1cc(OC)c(OCc2ccccc2)cc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 7.5 %

Procedure:
Propane-1-sulfonic acid [2-(2-amino-4-benzyloxy-5-methoxy-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide (133 mg, 0.27 mmoles) was dissolved in dichloromethane and triethylamine added (0.05 ml, 0.35 mmoles). The reaction was cooled and methanesulfonyl chloride (0.023 ml, 0.3 mmoles) added dropwise. The reaction was stirred for two hours and the product purified by flash chromatography (hexanes:ethyl acetate, 1:1). The product was then taken-up in ethanol and hydroxylamine hydrochloride (35 mg, 0.5 mmoles) added. Sodium ethoxide (48 mg, 0.7 mmoles was added and the reaction heated for 48 hours. The ethanol was removed and water (4 ml) added. The solid was filtered off and washed with water. The crude product was then taken up in 4 ml of methanol with 0.5 ml acetic acid. Raney Nickel (ca. 50 mg as a suspension in sodium hydroxide, Aldrich) was added and the reaction placed under a hydrogen atmosphere. The reaction was stirred vigorously for 3 hours and the catalyst filtered off. The crude product was submitted to reverse-phase preparative chromatography to yield the final product 4-[1-(4-Benzyloxy-2-methanesulfonylamino-5-methoxy-phenyl)-2-(propane-1-sulfonylamino)-ethylamino]-benzamidine (12 mg): MS (M+H)=590.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Yield: 103 %

Procedure:
Dissolve 5-bromo-2-fluoronitrobenzene (28.8 mmol, 3.55 mL), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (28.8 mmol, 4.96 g), and triethylamine (35.9 mmol, 5.00 mL) in ethyl acetate (100 mL) and reflux under nitrogen for 48 h. Cool to room temperature. Wash with 0.5 M hydrochloric acid twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain a bright orange solid (11.04 g, >100%). LC-MS m/z (79Br/81Br) 394.0/396.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:26](OC(C)C)(C)C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1c[nH]c2cc(Br)ccc12
Reactant: CC(C)OC(C)C
Product: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1cn(C)c2cc(Br)ccc12

Procedure:
The subtitle compound was prepared following the procedure of Example 92(d), using methyl 2-(6-bromo-1H-3-indolyl)-2-(6-chloro-1,3-benzodioxol-5-yl)acetate from step (c). m.p. 183-185° C. from diisopropyl ether.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)C4CNCC[C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.IC>CN(C=O)C.O1CCOCC1>[CH3:1][N:3]1[CH2:6][CH2:7][C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:8][CH:9]=[N:10][CH:11]=4)=[CH:14][CH:15]=3)[N:21]=[C:22]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:5]=2[CH2:4]1
Reactant: c1ccc(Nc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(Nc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Triethylamine (0.022 mL, 0.16 mmol) was added to N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.06 g, 0.16 mmol, Example 3) in DMF (1 mL) and dioxane (1 mL). Iodomethane (0.031 g, 0.22 mmol) was added and the reaction stirred at 25° C. for 1 h. Solvent was removed under reduced pressure and the crude product redissolved in DMSO. The crude product was purified by preparative HPLC to give 6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.014 g, 23%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:31][CH2:30][CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:32])=[O:8])=[CH:2]1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(O)c1cc[nH]c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCNC(=O)c1cc[nH]c1)OCc1ccccc1
Yield: 88.6 %

Procedure:
Using 1.67 g (15 mmol) of 3-pyrrolecarboxylic acid, 6.33 g (18 mmol) of β-alanine benzyl ester p-toluenesulfonate, 2.94 g (18 mmol) of diethyl phosphorocyanidate, 3.64 g (36 mmol) of triethylamine and 50 ml of DMF, 3.62 g of the title compound were obtained in a similar manner as in Example 1 (yield: 89%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([NH:23][C:24]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:30])[CH2:22][O:21][CH2:20]4)[CH:14]=3)[N:11]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)[nH]n3)c2)COC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C2(NC(=O)OC(C)(C)C)COC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl {3-[3-(5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}carbamate (98 mg, 0.21 mmol), ethyl bromoacetate (80 mg, 0.47 nimbi), and potassium carbonate (67 mg, 0.48 mmol) were combined in 0.5 mL of DMF and the mixture was stirred at ambient temperature under argon atmosphere for 4 h, then warmed to 60° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 12 g silica gel column using 0-5% MeOH:CHCl3 over 16 min at 30 mL/min. The fractions containing the first-eluting product were combined and evaporated under reduced pressure to give ethyl [3-(4-trifluoromethylphenoxy)-5-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (product A) as an oil, calcd (M+1)+: 562.6. Found: 562.2. 1H NMR (400 MHz, CDCl3) δ 7.6 (m, 5H), 7.50 (t, J=7, 1H), 7.37 (d, J=7, 1H), 7.29 (s, 1H), 5.99 (s, 1H), 5.85 (br s, 1H), 5.00 (d, J=5, 2H), 4.85 (br d, 2H), 4.79 (s, 2H), 4.21 (q, J=7, 2H), 1.27 (t, J=7, 3H). The fractions containing the second-eluting product were combined and evaporated under reduced pressure to give ethyl [5-(4-trifluoromethylphenoxy)-3-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (product B) as an oil, calcd (M+1)+: 562.6. Found: 562.9. 1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1H), 7.6 (m, 3H), 7.50 (d, J=7, 1H), 7.42 (t, J=7, 1H), 7.32 (d, J=6, 2H), 6.03 (s, 1H), 5.82 (br s, 1H), 5.00 (br s, 2H), 4.90 (overlapping brs s and sharp s, 4H), 4.21 (q, J=7, 2H), 1.25 (t, J=7, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[CH:35]1([C:38]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:6][CH:5]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)C3CC3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate with cyclopropanecarbonyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-cyclopropylcarbonyloxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 572 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:17][CH:18]=[C:19]([C:24]([O:26]C)=O)[C:20]([O:22][CH3:23])=[O:21])=[O:5].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:26]=[C:24]1[N:11]2[CH:12]=[N:13][C:14]3[CH:15]=[CH:16][C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:28])([CH3:1])[CH3:29])=[CH:8][C:9]=3[C:10]2=[N:17][CH:18]=[C:19]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)CC(C)(C)C)cc12)C(=O)OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NC(=O)CC(C)(C)C)ccc3ncn2c1=O
Temperature: 260 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
A mixture of dimethyl [{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate (7.30 g) and diphenylether (44 ml) was stirred at 260° C. for 10 minutes and then cooled to ambient temperature. To the mixture was added hexane to give crystals, which were filtered off and washed with hexane to give crystalline methyl 4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (6.28 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH2:53][CH2:54]N2CCC(C3C=CC=CC=3[S@](C)=O)CC2)[CH2:35][N:36]([CH3:52])[C:37]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[C:41]([N+:49]([O-:51])=[O:50])[CH:40]=2)=[O:38])=[CH:30][CH:29]=1>O>[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH2:53][CH2:54][N:11]2[CH2:12][CH2:13][CH:8]([N:3]3[CH2:4][CH2:5][CH2:6][NH:7][C:2]3=[O:1])[CH2:9][CH2:10]2)[CH2:35][N:36]([CH3:52])[C:37]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[C:41]([N+:49]([O-:51])=[O:50])[CH:40]=2)=[O:38])=[CH:32][CH:33]=1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN(CC(CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)cc1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: CN(CC(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)cc1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
Using standard reductive amination conditions 4-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)piperidine (Miller, S C; Jacobs, R T; Shenvi, A B. EP 739891) was reacted with N-[2-(4-chlorophenyl)-4-oxobutyl]-N-methyl-3-nitro-1-naphthamide [Example 3] and converted to the citrate salt. MS m/z 578 (M+H). Analysis for C31H36ClN5O4.1.0 C6H8O7.0.8 H2O: calculated: C, 56.64; H, 5.86; N, 8.92; found: C, 56.60; H, 5.74; N, 8.69.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[S:24]1(=[O:34])=[O:33]>>[O:33]=[S:24]1(=[O:34])[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Product: O=C1CCc2ccccc2N1C1CCN(CCCCN2C(=O)c3ccccc3S2(=O)=O)CC1

Procedure:
From the hydrochloride salt of 3,4-dihydro-1-(4-piperidyl)-2(1H)-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained 1,1-dioxido-2-(4-(4-(3,4-dihydro-2-oxo-(1H)-quinolin-1-yl)-piperidin-1-yl)-butyl)-1,2-benzisothiazol-3(2H)-one as a white solid: 1H NMR (300 MHz, CDCl3) 8.07 (dd, J=6.5, 2.3 Hz, 1H), 7.92 (t, J=6.73 Hz, 1H), 7.84 (m, 2H), 7.21 (t, J=8.73 Hz, 2H), 7.19 (m, 1H), 6.99 (t, J=7.13 Hz, 1H), 4.35 (tt, J=12.2, 4.2 Hz, 1H), 3.83 (t, J=7.32 Hz, 2H), 3.04 (d, J=11.42 Hz, 2H), 2.81 (t, J=6.59 Hz, 2H), 2.61 (m, 3H), 2.43 (t, J=7.19 Hz, 2H), 2.09 (t, J=11.71 Hz, 2H), 1.88 (m, 2H), 1.69 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][CH3:31])=[O:4].C([O-])(O)=O.[Na+].O.CCOC(C)=O>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][CH3:31])=[O:4]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OC(C)=O)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
(3S,8S)-3-(4-Acetoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (120 mg) was dissolved in methanol (5 mL). To this solution was added NaHCO3 (400 mg). The mixture was stirred at rt for 2-3 h. After completion of the reaction, the mixture was poured into water (10 mL) and was extraxcted with EtOAc (30 mL). The organic layer was washed with water, brine, dried and concentracted to get the desired product as a white solid (110 mg) LCMS (m/z): 461.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:2].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[Cl-].[Na+].O>[Br:22][CH2:14][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOc1ccc(C)c(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(CBr)c(C(=O)OC)c1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
To a solution of methyl 5-ethoxy-2-methylbenzoate (134b, 0.700 g, 3.61 mmol) in CCl4 (12 mL) was added BPO (18.0 mg, 0.0720 mmol) and NBS (0.706 g, 3.97 mmol) at room temperature. The resulting mixture was heated at 80° C. for 12 hours under N2 atmosphere. The mixture was diluted with CH2Cl2 (10 mL) and brine (3 mL). The organic layer was separated and washed with NaHCO3 (2 N, 10 mL), H2O (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to give methyl 2-(bromomethyl)-5-ethoxybenzoate (134c, 0.85 g, 86%) as yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:14])[CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>O1CCCC1.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.[Cu]I>[F:1][C:2]1[C:12]([C:16]#[C:15][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:14])[CH:3]=1
Reactant: C#Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CCOC(=O)c1cc(I)c(F)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)c(F)cc1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (3.6 g, 80%, 10 mmol), 4-ethynyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (2.7 g, 10 mmol) and triethylamine (5 g, 50 mmol) were suspended in tetrahydrofuran (20 ml) and the mixture heated to 50° C. Dichlorobis(triphenylphosphine)palladium (45 mg, 0.06 mmol) and copper(I)iodide (76 mg, 0.4 mmol) were added with stirring. After about 15 min a practically clear solution had formed. After 3 h at 50° C. the solution was taken to dryness and triturated with isobutylmethylketone and dilute hydrochloric acid. The organic phase was separated and the solvent evaporated. The oily residue was triturated with a small amount of acetonitrile to form crystals. These were recrystallized from acetic acid. The product was dissolved in a small amount of chloroform and the solution applied on top of a short silica gel column and eluted with 25% isobutylmethylketone in toluene. The pure product resulted after evaporation of the solvent. Yield 2.0 g, 44%.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cc(C(F)(F)F)ccc3F)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)nccc12
Yield: 79.3 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 1-(2-fluoro-5-(trifluoromethyl)phenoxy)-5-nitroisoquinoline (320 mg, 0.90 mmol), iron powder (500 mg, 9.09 mmol), and NH4Cl (389 mg, 7.2 mmol) in EtOH (8 mL) and water (2 mL) to afford 230 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.89 (d, J=5.7 Hz, 1H), 7.75-7.59 (m, 4H), 7.50 (d, J=7.8 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.03 (s, 2H); MS (m/z): 323.28 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-])=O)[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[O:17][CH3:18])([O-:3])=[O:2].[PH2]([O-])=O.[Na+]>[Pd].O1CCCC1.O>[NH2:12][C:8]1[C:9]([O:10][CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:17][CH3:18])=[CH:6][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(OC)c([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c([N+](=O)[O-])c(OC)c1N
Reaction time: 0.5 h

Procedure:
A suspension of 26 g of palladium on charcoal (10%) is refluxed in 1.3 l of tetrahydrofuran and 26 ml of water containing 1 mole (258 g) of 2,4-dinitro-1,3,5-trimethoxybenzene. A solution of 247 g of sodium hypophosphite in 260 ml of water is added to this suspension over 3 hours. Refluxing is continued for an additional 30 minutes. After cooling, the catalyst is removed by filtration and the aqueous phase by phase separation. The organic phase is concentrated under vacuum and is then poured onto ice. The expected product precipitates. It melts at 111° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]1[CH2:16][C:17]([OH:19])=O)[CH3:2].CCN(C(C)C)C(C)C.[N:29]1([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]1[CH2:16][C:17]([N:32]1[CH2:33][CH2:34][N:29]([C:35]2[N:36]=[CH:37][CH:38]=[CH:39][N:40]=2)[CH2:30][CH2:31]1)=[O:19])[CH3:2]
Reactant: CCn1cc(-c2ccc(F)c(C)c2)nc1CC(=O)O
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1CC(=O)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
50 mg (1-ethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl)-acetic acid was dissolved in 2 mL DMF. 100 mg PFTU and 60 μL DIPEA were added to this solution and the mixture was stirred for 10 min at RT. 160 mg 2-piperazin-1-yl-pyrimidine was added and the reaction was stirred over night. Then, potassium carbonate solution (5%) and dichlormethane were added, the organic layer was separated and the solvent was removed. The residue was purified by HPLC and crystallized with diisopropylether to give 55 mg of the desired compound.