Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].Br[CH:30]([F:32])[CH3:31]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH:30]([F:32])[CH3:31])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CC(F)Br
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)F)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 7 h
Yield: 61.7 %

Procedure:
A mixture of 3.2 g (0.011 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate and 4 g (2.5×0.011 mol) of potassium carbonate in 20 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 7 g (5×0.011 mol) of bromofluoroethane are added, the mixture is kept for 7 hours at 80° C., left to cool and poured into a water/ice mixture, and the precipitate formed is filtered off, washed with water and recrystallized from a dimethylformamide/water mixture (1:1) to give 2.35 g of a solid melting at 231°-234° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(N)CCO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)C(CCO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 3-amino-4-methyl-1-pentanol (CAN 26734-09-8) as starting materials and isolated (21 mg, 64%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 327.1473 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2=[O:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:3]([CH3:22])[C:4]([N:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1=[O:21])=[N:5]2
Reactant: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4,4-dimethylpyrrolidin-2-one (150 mg, 0.46 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-4,4-dimethylpyrrolidin-2-one. 1H NMR (CDCl3) δ ppm 8.11 (1H, d, J=1.8 Hz), 8.02 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=2.2 Hz), 7.45 (1H, dd, J=9.3, 1.1 Hz), 7.02 (1H, ddd, J=13.3, 8.6, 2.5 Hz), 6.82 (1H, t, J=2.2 Hz), 3.91 (2H, br. s.), 3.71-3.85 (4H, m), 3.25-3.39 (4H, m), 2.44 (2H, s), 2.09 (3H, s), 1.34 (6H, s). Mass Spectrum (ESI) m/e=468.3 (M+1).
Reaction SMILES: C([Li:5])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1>CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Li:5])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(Br)c1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 159 ml. of n-butyllithium in 100 ml. of hexane containing 47.7 g. of 3-methoxybromobenzene was stirred at -25° C. for twenty minutes and then was warmed to room temperature and stirred for one hour to provide 3-methoxyphenyl lithium. The reaction mixture was chilled to 10° C. and stirred while a solution of 50 g. of 1-methyl-4-piperidone in 100 ml. of diethyl ether was added dropwise over thirty minutes. Following complete addition, the reaction mixture was stirred for two hours, and then was diluted with 50 ml. of saturated aqueous sodium chloride solution. The solution was extracted several times with diethyl ether, and the ethereal extracts were combined and concentrated to dryness to provide 38 g. of 1-methyl-4-hydroxy-4-(3-methoxyphenyl)piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Se](=O)=[O:16]>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](=[O:16])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[Se]=O
Agent: O=C1CCCc2ccc([N+](=O)[O-])cc21
Product: O=C1C=Cc2ccc([N+](=O)[O-])cc2C1=O

Procedure:
7-Nitro-1-tetralone was prepared according to the literature (J. Am. Chem. Soc, 1994, 116, pp4852–4857). Treatment of 7-nitro-1-tetralone with selenium dioxide as described in Reference Example 1A yielded the corresponding 7-nitro-[1,2]naphthoquinone, which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]([CH2:16][CH:17]=[CH2:18])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
In a 250 mL round-bottomed flask, (S)-4-benzyl-3-(pent-4-enoyl)oxazolidin-2-one, Intermediate S8A (3.35 g, 12.92 mmol) was added to THF (40 mL) to give a colorless solution. The mixture was cooled in −78° C. bath for 10 min. Sodium bis(trimethylsilyl)amide (14.21 mL, 14.21 mmol) was added slowly to the reaction mixture. The reaction mixture turned a light orange color. The reaction mixture was stirred at −78° C. for 2 h. Then tert-butyl 2-bromoacetate (5.04 g, 25.8 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 3 hr. The reaction was quenched with saturated NH4Cl. The mixture was diluted with brine and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated to give a crude material that was purified on silica gel column (120 g ISCO) eluting with a gradient from 0-50% EtOAc/hexane. [The product showed weak UV absorption at 254 nm]. Tubes with product were collected and concentrated to afford (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate, Intermediate S8B (3.2 g, 8.40 mmol, 65.0% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.40-7.21 (m, 5H), 5.89-5.66 (m, 1H), 5.15-5.03 (m, 2H), 4.73-4.61 (m, 1H), 4.34-4.23 (m, 1H), 4.16 (d, J=5.1 Hz, 2H), 3.35 (dd, J=13.4, 3.1 Hz, 1H), 2.88-2.67 (m, 2H), 2.52-2.38 (m, 2H), 2.28-2.13 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:10]([I:11])=[C:9]([NH2:12])[C:8]([I:13])=[C:7]([NH2:14])[C:6]=1[I:15])[CH2:3][OH:4].C([O:19][CH2:20][C:21](Cl)=[O:22])(=O)C>>[OH:1][CH:2]([C:5]1[C:6]([I:15])=[C:7]([NH:14][C:2](=[O:1])[CH2:3][OH:4])[C:8]([I:13])=[C:9]([NH:12][C:21](=[O:22])[CH2:20][OH:19])[C:10]=1[I:11])[CH2:3][OH:4]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1c(I)c(N)c(I)c(C(O)CO)c1I
Product: O=C(CO)Nc1c(I)c(NC(=O)CO)c(I)c(C(O)CO)c1I

Procedure:
1-(1,2-Dihydroxyethyl)-3,5-diamino-2,4,6-triiodobenzene is acylated with acetoxyacetyl chloride using for example such a procedure as described in Example 4d. The crude product is then hydrolyzed analogous to Example 4e to give the final product. Purification of the crude product is carried out using preparative HPLC.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Br:17]Br.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)(Cl)Cl.ClCCl>[Br:17][C:2]1[S:1][C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To tert-butyl 4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (2.0 g, 8.4 mmol) in chloroform (100 mL) at 0° C. was added dropwise bromine (430 μL, 8.4 mmol). The reaction was stirred 45 min with gradual warming to room temperature. The mixture was cooled to 0° C., and triethylamine (1.2 mL, 8.4 mmol) was added followed by di-tert-butyl dicarbonate (913 mg, 4.2 mmol). The reaction was stirred 1 hour, diluted with dichloromethane (50 mL), washed with 1.0 N HCl (1×50 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting crude residue was purified via silica gel chromatography to afford 2 g (77% yield) of tert-butyl 2-bromo-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate as a colorless oil; 1H NMR (CDCl3) δ 6.78 (s, 1H), 4.50 (s, 2H), 3.67 (t, J=5.7 Hz, 2H), 2.65 (t, J=5.7 Hz, 2H), 1.50 (s, 9H); ES-MS: m/e=261.9 (M-55)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([Br:17])=[C:10]([CH3:18])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Br:17][C:11]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[CH3:18]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc([N+](=O)[O-])c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)cc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.8 %

Procedure:
(4-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid tert-butyl ester (1000 mg, 2.9 mmol) was dissolved into DCM (10 mL). To this was added TFA (10 mL) and the reaction was stirred at RT for 1 hour. The pH was adjusted to 8 with 1 N NaOH and the solvents were removed in vacuo. The reaction mixture was dissolved into EtOAc and the layers were separated. The organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in title compound (756 mg, quantitative) as a brown oil. 1H-NMR (CDCl3): δ 8.44 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 3.05 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][C:20](=[O:25])[C:21](Br)([CH3:23])[CH3:22])[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:25])[C:21]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:23])[CH3:22])[CH3:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C=O
Temperature: 140 °C
Yield: 68 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), KI (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 mL) was added 2-bromo-2-methyl-propionic acid ethyl ester (17.6 g, 90 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (15 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Cl:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][C@@H:45]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]([F:68])([F:67])[F:66])[CH2:46][N:47]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][C@@H:45]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])=[O:10])[S:5][C:6]=1[Cl:7]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1cc(Br)c(Cl)s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)c(Cl)s1
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-5-chloro-2-thiophenecarboxylic acid (1.3 g, 5.42 mmol), PyBrOP (3 g, 6.5 mmol) and diisopropylethyl amine (4.7 mL, 27.1 mmol) in DCM (54 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (2.0 g, 5.42 mmol)[prepared in Preparation 6]. After 1 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and used directly: LCMS (ES) m/z=572 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[N:8]=[C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]2[CH:18]=1.[C:19](=O)([O-])[OH:20].[Na+]>CN(C)C=O>[CH:19]([C:18]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]2=[N:8][C:7]=1[CH3:6])=[O:20]
Reactant: O=C([O-])O
Reactant: Cc1cn2cccc([N+](=O)[O-])c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c([N+](=O)[O-])cccn2c1C=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
20 ml phosphoroxychloride is added dropwise within 5 minutes to a solution of 7.6 g 2-methyl-8-nitro-imidazo[1,2-a]pyridine in 100 ml dimethylformamide at 0° C. After stirring for 1 hour at 0° C. and for 2 hours at 70° C. the mixture is cooled again to 0° C. 10 ml phosphoroxychloride is added dropwise and the same procedure is carried out as before. When the reaction is finished the mixture is poured over 200 ml icewater, neutralized with saturated sodium hydrogen carbonate solution and extracted 3×with 50 ml ethyl acetate each time. The solvent is stripped off in vacuo and the residue is washed with ether and recrystallized from acetronitrile, giving the title compound of m.p. 188°-189° C.
Reaction SMILES: ClC1C=CC(C2C3C=CC=CC=3C3=C(C)ON=C3C[N:9]=2)=CC=1.O[CH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[C:31]1[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:32]=1[C:33](OC)=[O:34].ClC1C=CC(C(C2C=CC=CC=2C2C(CO)=NOC=2C)=O)=CC=1.[N-]=[N+]=[N-]>CO>[CH3:42][O:41][C:39]1[CH:38]=[CH:37][C:32]2[C:33](=[O:34])[NH:9][CH2:24][C:25]3[O:29][N:28]=[C:27]([CH3:30])[C:26]=3[C:31]=2[N:40]=1
Reactant: COC(=O)c1ccc(OC)nc1-c1c(C)noc1CO
Reactant: Cc1onc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1onc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: COc1ccc2c(n1)-c1c(C)noc1CNC2=O

Procedure:
A reaction sequence similar to that used to prepare Compound 191 was followed, except that methyl 2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-6-methoxynicotinate was used as starting material instead of (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone and methanol was used as the co-solvent for the conversion of the azide to the lactam. LC/MS m/z 246 [M+H]+.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH2:13]([N:15]([CH2:19][CH3:20])[C:16](Cl)=[O:17])[CH3:14]>C1COCC1>[N+:3]([C:6]1[CH:7]=[C:8]([O:12][C:16](=[O:17])[N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCN(CC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.7 %

Procedure:
To slurry of 50% sodium hydride (340 mg, 14.2 mmol) in anhydrous THF was added 3-nitrophenol (1 g, 7.1 mmol) at 0° C. After 10 min at 0-5° C., diethyl carbamyl chloride (1.5 g, 111.0 mmol) was added and the reaction mixture heated to reflux for 12 hr. The reaction mixture was cooled, ice water added, and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography over silica gel, using hexane/ethyl acetate (85:15) as eluent to afford diethyl-carbamic acid-3-nitro-phenyl ester (300 mg, 17%).
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:8][CH:9]([O:31][CH2:32][CH3:33])[C:10]1[N:14]2[C:15]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH2:19][C:13]2=[N:12][N:11]=1)[CH3:7]>CC(C)=O.CO>[CH2:32]([O:31][CH:9]([O:8][CH2:6][CH3:7])[C:10]1[N:14]2[C:15]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH2:19][C:13]2=[N:12][N:11]=1)[CH3:33].[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCOC(OCC)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CC(C)=O
Solvent: CO
Product: [O-][Cl+3]([O-])([O-])[O-]

Procedure:
An amount of 0.13 g (0.0013 mole) of perchloric acid is added to a solution of 0.5 g (0.00126 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3 -a][1,4]benzodiazepine-1-carboxaldehyde-diethylacetal in 3 ml each of acetone and methanol. The salt crystallises out after the addition of 5 ml of petroleum ether. Filtration under suction is then performed and 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde-diethylacetal-perchlorate obtained, which decomposes at 250°-265°.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CNCCNC1
Product: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure D.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
94 mg of solid yellow 3-{4-[3-(4-trifluoromethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>CS(C)=O>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: Cc1ccc(O)c(B(O)O)c1
Solvent: CS(C)=O
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenylboronic acid in 50% yield using method F; δH [2H6]]-DMSO 13.27,(1H, b), 12.64,(1H, b), 8.37,(1H, d), 8.33,(1H, d), 8.21,(2H, t), 8.14,(2H, d), 7.93,(1H, s), 7.64,(1H, s), 7.17,(1H, d), 7.00,(1H, d), 6.93,(1H, d), 6.89,(1H, d), 3.82,(3H, s), 2.34,(3H, s).
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1
Reactant: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(F)cc1
Reactant: Cc1ncc(Br)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.90 mL, 2.2 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (408.9 mg, 2.336 mmol) in dry THF (12 mL) in a dry ice-acetone bath. After 1-2 minutes, (4-chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.505 g, 1.16 mmol, Intermediate 48: step b) in dry THF (12 mL) was added to the mixture via syringe. After 5 minutes, the reaction was removed from the cold bath and was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the aqueous mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM). Due to remaining impurities, the material was dissolved in ethyl acetate and washed several times with minimal water. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness. The material was purified by reverse phase chromatography (acetonitrile/H2O+0.05% TFA), basified with saturated aqueous sodium bicarbonate, and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=2.2 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28-7.24 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.96-6.89 (m, 3H), 6.00 (s, 1H), 4.23 (s, 2H), 4.07 (s, 3H), 3.36 (s, 3H), 2.51 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H); MS m/e 531.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[C:29]([Cl:33])=[CH:28][N:27]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#CCNC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 48 h
Yield: 3.9 %

Procedure:
2-Amino-N-prop-2-ynyl-benzamide (4.20 g, 24.1 mmol) was dissolved in N,N-dimethylformamide (100 mL, 1.290 mol) and potassium carbonate (5.00 g, 36.2 mmol) was added. 2,4,5-Trichloro-pyrimidine (3.32 mL, 28.9 mmol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and the residue was taken up in DCM (300 mL) and washed with water (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide as a pale yellow solid (298 mg, 4%). m.p.=188-191° C.; LCMS (m/e) 321 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.53 (s, 1H), 8.76 (d, 1H, J=8.5 Hz), 8.25 (s, 1H), 7.66-7.53 (m, 2H), 7.23-7.14 (m, 1H), 6.39 (bs, 1H), 4.34-4.25 (m, 2H), 2.34 (t, 1H, J=2.5 Hz).