Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@@H:3]([OH:14])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[CH:18][CH:17]=1.N1C(C)=CC(C)=CC=1C.C(O)C>C1(C)C=CC=CC=1.C(O)CCC>[OH:14][C@H:3]([CH2:2][NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[CH:20][CH:21]=1)[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7]
Reactant: O=C(NC[C@H](O)CBr)c1ccc(Cl)s1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Temperature: 104 °C

Procedure:
55 g of N-((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) and 29.4 g of 4-(4-aminophenyl)-3-morpholinone (III) (a preparation method is described, for example, in WO-A 01/47919 on pages 55 to 57) are suspended at from 20 to 25° C. in 500 ml of toluene and admixed with 18.5 g of collidine and 10 ml of ethanol. The reaction mixture is heated to from 103 to 105° C. for 6 hours and then admixed while hot with 50 ml of 1-butanol. After cooling to 30° C., the precipitated reaction product is filtered off with suction, washed with toluene and water and dried.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[C:11]([Cl:17])=[CH:12][C:13]=1[Cl:16]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Br)c2n1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-bromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (110 mg, described in Example 55). MS (ES): M/Z [M+H]=552. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.44 (d, J=13.3 Hz, 1H), 5.60 (d, J=13.7 Hz, 1H), 7.75-8.04 (m, 5H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:11]([N+:20]([O-])=O)=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH3:19])=[CH:13]3)[CH:5]=[CH:4][C:3]=1[CH2:23][C:24]([OH:26])=[O:25].O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH3:34]O>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[NH2:20][C:11]1[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:23][C:24]([O:26][CH3:34])=[O:25])=[C:2]([CH3:1])[C:7]=2[CH3:8])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:19])[NH:15]2
Reactant: CO
Reactant: Cc1cc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(C)c1C
Temperature: 60 °C

Procedure:
Under an N2 atmosphere, 2-(2,3-dimethyl-4-(2-methyl-4-nitro-1H-indol-5-yloxy)phenyl)acetic acid (0.335 g, 0.946 mmol) was suspended in methanol and tin chloride dihydrate (1.71 g, 7.57 mmol) was added. The reaction was heated to 60° C. for 16 h. The reaction was diluted with ethyl acetate and 10% NaHCO3 (aq). The layers were separated and the organic layer was washed with water (3×), dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 20% to 80% ethyl acetate in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 339.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6])([O-:13])=[O:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 3-bromo-5-nitro benzoic acid (1 g, 4.06 mmol) and 2-fluoro-phenyl boronic acid (569 mg, 4.06 mmol) in dimethoxyethane (20 ml) and EtOH (1 ml) was added Na2CO3 (7 ml saturated solution) and palladium tetrakis(triphenylphosphine) (94 mg, 0.08 mmol). The mixture was heated at reflux for 4 h and then stirred at RT for 16 h. The grey precipitate that formed was filtered off and washed with CH2Cl2. The filtrate was evaporated, affording 3-nitro-5-(2-fluorophenyl)benzoic acid (intermediate XXXIVj, 880 mg, 83% yield) as a white solid. M+=262.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][C:6]=2[Br:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1.CCN(CC)CC>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH:13][C:23]([C:22]1[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=1)=[O:24])=[CH:7][C:6]=2[Br:14]
Reactant: NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
[(2-Trifluoromethyl-7-bromo-1H-indol-5-yl)methyl]amine (Intermediate 9, 230 mg, 0.785 mmol) was dissolved in DCM (10 mL) and 6-(trifluoromethyl)nicotinoyl chloride (ABCR; 181 mg, 0.863 mmol) was added. Et3N (0.219 mL, 1.570 mmol) was added and the reaction mixture was then left to stir at room temperature for 30 min. The reaction mixture was quenched with water then the organic layer was collected, dried (MgSO4), filtered and evaporated to dryness. The resulting residues were purified by MDAP to give the title compound, (200 mg);
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37]>N.CO>[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.2 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-Methylbenzenesulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.0 mg). MS m/z 343 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:38][C:39]([F:50])([F:49])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([C:39]([F:50])([F:49])[F:38])[CH:45]=2)[C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 3-(trifluoromethyl)phenylboronic acid to afford the desired product as a colorless foam (67%). MS (ISP): 675.2 (M+H)+.
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH2:19]Cl.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH2:19][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1c(C)cc(C)cc1C

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 2,4,6-trimethylbenzyl chloride (10.25 g), a 2M ethanolic solution of sodium ethylate (32.5 cc) and ethyl 2-mercaptoacetate (7.1 g) in ethanol (150 cc). Ethyl (2,4,6-trimethylbenzylthio)acetate (11 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: CC(N([C@H](C)C(NC1C=NC(OC2C=CC=C(C(C)C)C=2)=CC=1)=O)C(=O)[O-])(C)C.CC([N:34]([C@H:38]([CH3:58])[C:39]([NH:41][C:42]1[CH:43]=[N:44][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:50]=2[CH3:57])=[CH:46][CH:47]=1)=[O:40])C(=O)[O-])(C)C>>[CH3:57][C:50]1[C:51]([O:55][CH3:56])=[CH:52][CH:53]=[CH:54][C:49]=1[O:48][C:45]1[N:44]=[CH:43][C:42]([NH:41][C:39](=[O:40])[C@@H:38]([CH3:58])[NH2:34])=[CH:47][CH:46]=1
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1C
Agent: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Product: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Yield: 117.2 %

Procedure:
The title compound (268 mg) was made in a similar fashion to the preparation of Intermediate 26 replacing 1,1-dimethylethyl{(1R)-1-methyl-2-[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate with 1,1-dimethylethyl{(1R)-1-methyl-2-[(6-{[2-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 62, 304 mg). Instead of being stirred at 0° C. for 3 hours, the reaction was stirred at 0° C. for 1 hour and at room temperature for 2 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:15][CH2:14][CH2:13]N(CCCC)CC[O:9]1.[Li][CH2:21]CCC.CC(C)=O.Cl>C1COCC1>[CH3:21][C:14]1([CH3:13])[O:15][B:8]([OH:9])[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: [Li]CCCC
Reactant: CCCCN1CCOB(c2ccccc2Br)OCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 2-(2′-bromophenyl)-6-butyl[1,3,6,2]dioxazaborocan (93.1 g, 277.1 mmol) in THF (2.3 L) at −78° C. was added n-BuLi (133.0 mL, 2.5M in hexane, 332.5 mmol, 1.2 equiv.) dropwise via a syringe over a period of 10 min while maintaining reaction temperature at −78° C. After the addition the reaction solution was stirred for 20 min at −78° C. before acetone (23.2 mL, 387.9 mmol, 1.4 equiv.) was added dropwise via a syringe over a period of 10 min while maintaining the reaction temperature at −78° C. The resulting mixture was allowed to stir for 20 min at −78° C. then warm to room temperature gradually. Once the reaction vessel reached room temperature, 6N HCl solution (1 L) was added and the mixture was stirred for an additional 30 min. The mixture was extracted with EtOAc (3×). The EtOAc extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The light yellow oil was then subjected to flash chromatography (Isco Companion, 80 g SiO2 cartridge, solid loaded SiO2, neat heptanes to 20:80 EtOAc gradient at 60 ml/min for 90 min). The title compound was recovered as clear colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 6 H) 7.31 (d, J=1.1 Hz, 1 H) 7.38-7.47 (m, 2 H) 7.66 (d, J=7.2 Hz, 1 H) 8.99 (s, 1 H). Amount obtained: 16.9 g (37.7% yield).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[F:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ccccc1S
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1cc(Sc2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.3 %

Procedure:
To 2.2 ml of chloroform were added 0.29 ml of diisopropylethylamine, 0.2 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.17 g of 2-fluorothiophenol, followed by stirring at room temperature for 7 hours. Then, a saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-butynyloxy)-6-(2-fluorophenylthio)pyrimidine (the present compound (146)).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:23]([C:28](O)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[NH:22]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:23]([C:28]([NH:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 18 h
Yield: 72.7 %

Procedure:
In 200 ml of 1.5N NEM/DMF mixture, 45.2 g (0.2 mol) of H-Lys(Z)-CHA.HCl was dissolved, and 35.3 g (0.1 mol) of BOC-Leu-SDP was added thereto at 0° to 5° C. The reaction was carried out at room temperature for 18 hours. After the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 1500 ml of AcOEt and washed with 500 ml of a cooled 5% HCl solution twice, and 500 ml of a saturated saline solution twice, followed by decoloration and drying over anhydrous magnesium sulfate and active carbon. After drying, the magnesium sulfate and active carbon were filtered and the solvent was removed by distillation under reduced pressure to yield crude BOC-Leu-Lys(Z)-CHA. This was recrystallized from a mixed solvent of AcOEt/ether/n-hexane to give 35.9 g (57.1%) of BOC-Leu-Lys(Z)-CHA.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C=O.O>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(CNc1ccncc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(CN(C(=O)OCc1ccccc1)c1ccncc1)OCC
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
A solution of 4-pyridylaminoacetaldehyde diethyl acetal (7.0 g.) in a mixture of dried dimethylformamide (20 ml.) and dried hexamethylphosphoric triamide (7.5 ml.) was dropwise added over 5 minutes under ice-cooling and stirring to a suspension of 65.5% sodium hydride (2.0 g.) in dried dimethylformamide (3 ml.). The mixture was stirred for 10 minutes at ambient temperature, for 30 minutes at 60° C and for 15 minutes under ice-cooling. A solution of benzyl chloroformate (9.0 g.) in dried dimethylformamide (2 ml.) was dropwise added thereto under stirring and ice-cooling. The resulting mixture was stirred for 20 minutes under ice-cooling and for 15 minutes at ambient temperature. After water was dropwise added to the reaction mixture, the mixture was extracted 3 times with ethyl acetate. The extract was in turn washed twice with water and once with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on silica gel (60 g.) using a mixture of benzene and ethyl acetate (7 : 3) as developing solvent to give oil of N-benzyloxycarbonyl-N-(4-pyridyl)aminoacetaldehyde diethyl acetal (1.3 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=O.[CH2:16]=[CH:17][CH:18]=[CH2:19]>>[OH:3][NH:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21

Procedure:
5-Nitro-1,4-naphthoquinone, referred to hereinafter for short as 5-nitronaphthoquinone, is an important dyestuff intermediate which is reacted with butadiene by a Diels-Alder reaction to 5-nitro1, 1,4,11,12-tetrahydroanthraquinone (q.v. for example N.N. Vorozhtsov et al., Zhur. Vsesoyuz. Khim. Obshchestva in D.I. Mendeleeva 5, 474 (1960) - Chem. Abstract, Vol. 55, 1547e), which is subsequently rearranged to give 1-hydroxyaminoanthraquinone or converted direct to 1-aminoanthraquinone, the starting material for numerous disperse and vat dyes (e.g. German Offenlegungsschrift 24 50 883).
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][CH2:12][CH2:13][NH:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]([CH2:13][CH2:12][OH:11])[NH2:15])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
1-Fluoro-4-nitrobenzene (7.1 g, 50 mmol) was dissolved in CH3CN (70 ml), 2-hydroxyethylhyrazine (purity: 90%, Aldrich, 5.0 g, 66 mmol) and K2CO3 (7.6 g, 55 mmol) were added thereto. The suspension thus obtained was stirred for 4 hrs with reflux. The resulting orange-colored suspension was concentrated under reduced pressure (reflux condenser, 10 torr, 40° C.) and ethylacetate (EA, 90 ml) and water (18 ml) were added thereto. The resulting mixture was stirred strongly at r.t. for 10 min. The organic layer was extracted and washed with the saturated brine (10 ml). The resulting solution was cooled to 10° C. and 48% HBr solution (3.7 ml) was added thereto dropwise with stirring. The pale yellow colored solid thus obtained was filtered off and dried under high vacuum (1 torr, 40° C.) to obtain the title compound as an intermediate.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[S:9][C:10](/[CH:13]=[CH:14]/[N+:15]([O-])=O)=[CH:11][CH:12]=1.O.[OH-].[Na+]>C(OCC)C>[CH3:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:12]=1
Reactant: Cc1ccc(/C=C/[N+](=O)[O-])s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CCN)s1
Temperature: 0 °C
Yield: 20.1 %

Procedure:
To a suspension of 6.9 g (40.78 mmol) LiAlH4 in 70 mL diethyl ether under nitrogen was added drop wise a solution of 6.9 g (175 mmol) 2-methyl-5-((E)-2-nitro-vinyl)-thiophene in 150 mL diethyl ether at 20 to 25° C. After complete addition the mixture was heated to reflux for 5 h. The mixture was cooled to 0° C. and 28 mL water and 7 mL 5N NaOH and was added. The white solid was filtered, washed with ethyl acetate and the filtrate was concentrated in vacuo. The residue was distilled at reduced pressure to yield 4.98 g (86%) of the title compound as colourless liquid.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][O:9][C:3]2[C:2]([C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cnn(C)c2)nc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (MM3) (400 mg, 1.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (420 mg, 2.0 mmol), tripotassium phosphate (600 mg, 2.8 mmol), S-Phos (46 mg, 0.1 mmol), and Pd(OAc)2 (12.6 mg, 0.6 mmol) in THF (4.8 mL) and water (0.8 mL) was heated at 100° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and then diluted with EtOAc (10 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a colorless gum. 1H NMR (500 MHz, DMSO): δ 8.73 (s, 1 H), 8.14 (s, 1 H), 8.11 (s, 1 H), 7.97 (s, 1 H), 7.31-7.24 (m, 2 H), 4.54 (dd, J=11.2, 6.8 Hz, 1 H), 4.33 (dd, J=11.3, 7.7 Hz, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 2.50 (s, 3 H), 2.22 (dd, J=8.6, 4.7 Hz, 1 H), 1.79 (s, 1 H), 1.22-1.17 (m, 1 H), 1.10-1.05 (m, 1 H); HRMS m/z (M+H) 352.1761 found, 352.1768 required.