Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([O:3][CH2:4][CH3:5])=[O:2].[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:9]([C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:22])=[C:19]([NH2:20])[NH:21][C:19]=1[NH2:20])=[O:22])[CH3:15]
Reactant: CCOC(=O)c1cccc(C=O)c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc(C(=O)OCC)c1
Yield: 32 %

Procedure:
Upon boiling a solution of 8.9 g 3-carbethoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 100 ml ethanol for 2 hours, 2,6-diamino-4-(3-carbethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 191°C (ethanol) is obtained. Yield: 32% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH:15]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Oc2cncc(Br)c2)ccc1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
The reaction and post-treatment were carried out according to Example (1a) using 5-bromo-3-hydroxypyridine (5.01 g, 28.8 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (US200216506 A1, 7.50 g, 26.2 mmol), sodium hydride (63%, 1.10 g, 28.8 mmol) and DMF (87 mL) to obtain the title compound (11.1 g, 99%) as a yellow brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[CH2:14][NH:15][C:16]([C:18]1[S:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:17].[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:12]1[CH2:13][C:9](=[O:8])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:11]1)=[O:33]
Reactant: O=C(NC[C@@H]1CNCC1=O)c1ccc(Cl)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1

Procedure:
81.3 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-4-oxo-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale brown solid. MS 489.0 ([M+H]+)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(-n2c3ccccc3c3ccccc32)cc1

Procedure:
A mixture of 334.4 (2 mol) of carbazole, 472.8 g of p-chloro-nitrobenzene (3 mol) and 691 g (5 mol) of anhydrous potassium carbonate were stirred in 1500 ml of dimethylacetamide for 13 h at reflex temperature. The reaction mixture was then poured into 7 of water and the precipitate separated by suction filtering. Said precipitate was stirred in 4 of water and neutralized with 1 N hydrochloric acid, whereupon the precipitate was filtered again. After drying the solid product was recrystallized from a mixture of tetrahydrofuran and methanol and the yellow product obtained was dried. Yield: 465 g. Melting point: 211° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]([NH2:18])=[S:17].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC1C=CC(C)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[NH:18][C:16](=[S:17])[NH:15][C:10](=[O:12])[CH:9]=2)=[CH:3][CH:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccc(C)cc1
Product: O=c1cc(-c2ccncc2)[nH]c(=S)[nH]1

Procedure:
Ethyl isonicotinoylacetate (5 g, 25.89 mmol) and thiourea (5.94 g, 77.64 mmol) were suspended in anhydrous p-xylene (100 ml) with vigorous stirring. To the mixture, pyridinium p-toluenesulfonate (150 mg) was added and refluxed for 12-16 h using a Dean-Stark apparatus with continuous removal of water (0.5 ml). The reaction mixture was cooled and a dark brown solid was filtered. The collected solid was suspended in acetone (25 ml) and filtered. The acetone washed product contain trace of thiourea, which was removed by trituration with hot water (20-30 ml). The title compound was isolated by filtration. MS (m/z): 206.2 C9H7N3OS requir. 205.3. 1H-NMR (DMSO-d6): d 12.65 (bm, 2H, NH and SH), 8.71(m, 2H, pryid.), 7.66(m, 2H, Pyrid.), 6.25 (s, 1H, H-5).
Reaction SMILES: C([NH:9][C:10]([N:12]1[CH2:26][CH2:25][C:24]2[C:15](=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]=2[CH3:27])[CH2:14][CH2:13]1)=[S:11])(=O)C1C=CC=CC=1>[OH-].[Na+]>[C:10]([N:12]1[CH2:26][CH2:25][C:24]2[C:15](=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]=2[CH3:27])[CH2:14][CH2:13]1)(=[S:11])[NH2:9]
Reactant: Cc1c2c(nc3ccccc13)CCN(C(=S)NC(=O)c1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Product: Cc1c2c(nc3ccccc13)CCN(C(N)=S)CC2
Yield: 36 %

Procedure:
3-Thiocarbamoyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by hydrolysis of 3-(benzamido-thiocarbonyl)-1,2,4,5-tetrahydro-11-methyl-azepino[4,5-b]quinoline (m.p. 175° C) in 2 N sodium hydroxide at room temperature. Yield: 36 % of theory; m.p. 218° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.[NH:31]1[C:40]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35][C:34]=2[CH:33]=[N:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:31]1[C:40]2[CH2:39][CH2:38][N:37]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:21]=3)=[O:28])[CH2:36][CH2:35][C:34]=2[CH:33]=[N:32]1
Reactant: c1n[nH]c2c1CCNCC2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cn[nH]c5CC4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 mg (0.16 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 35 mg (0.20 mmol) 1,4,5,6,7,8-hexahydro-pyrazolo[4,3-d]azepine hydrochloride in 80 μL (0.57 mmol) TEA and 0.80 mL DMF were combined with 68 mg (0.18 mmol) HATU and the mixture was stirred overnight at RT. Then the reaction mixture was purified twice by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:19]=[O:20])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:19]=[O:20])=[C:4]2[N:3]=1
Reactant: Clc1ccn2nccc2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine (5.0 g, 32.5 mmol) in DMF was added POCl3 (7.5 mL, 81.2 mmol). The mixture was stirred at room temperature overnight. Ice was added to quench POCl3, then the mixture was neutralized with 1M NaOH. The resulting yellow precipitate was filtered and dried to yield 4.85 g (82% yield) of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde as yellow solid. LCMS (M+1=182)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([C:8]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[C:17]3[C:9]=2[C:10]2[CH2:11][CH2:12][CH:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:14][C:15]=2[NH:16]3)[CH:5]=[CH:6][CH:7]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](Cl)=[O:44]>C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:43](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)[C:3]=2[CH3:35])=[C:9]2[C:17]=1[NH:16][C:15]1[CH2:14][CH:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:12][CH2:11][C:10]2=1)(=[O:23])[NH2:22]
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3
Agent: Cl
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccccn2)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3

Procedure:
A solution of benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, TFA salt (Example 51-1, 55 mg, 0.094 mmol), TEA (0.066 mL, 0.472 mmol), and picolinoyl chloride hydrochloric acid salt (50.4 mg, 0.283 mmol) in DCM (8 mL) was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC to provide benzyl 8-carbamoyl-5-(2-methyl-3-(picolinamido)phenyl)-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, isolated as the TFA salt, as a white solid (26 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 8.59 (1 H, t, J=4.8 Hz), 8.14 (1 H, d, J=8.3 Hz), 7.89-7.99 (1 H, m), 7.85 (1 H, dd, J=9.9, 8.1 Hz), 7.50 (2 H, dd, J=7.7, 2.0 Hz), 7.11-7.32 (6 H, m), 7.01 (1 H, d, J=7.9 Hz), 6.74 (1 H, d, J=7.5 Hz), 4.96 (2 H, s), 3.68-3.87 (1 H, m), 2.96-3.10 (1 H, m), 2.49-2.66 (1 H, m), 1.82-2.11 (5 H, m), 1.73 (1 H, br. s.), 1.34-1.62 (1 H, m). Mass spectrum m/z 575.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:16]1[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=3[CH:15]=2)=[CH:2][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: Cn1c(=O)sc2ccc(C(=O)CBr)cc21
Reactant: Nc1ccccn1
Product: Cn1c(=O)sc2ccc(-c3cn4ccccc4n3)cc21
Yield: 28.7 %

Procedure:
5-(Imidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (0.65 g) was prepared in the substantially same manner as that of Example 4 from 5-(2-bromoacetyl)-3-methyl-2-benzothiazolinone (2.3 g) and 2-aminopyridine (2.3 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[O:11][N:10]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[O:11][N:10]=1
Reactant: COc1ccccc1-c1noc2ccsc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1noc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 23 g of 3-(2-methoxyphenyl)thieno[2,3-d]isoxazole in 450 ml of dichloromethane was added a boron tribromide solution in dichloromethane (150 ml, 1M solution) over one hour. The reaction mixture was stirred for an additional one hour at room temperature and then poured over 600 ml of ice water. A precipitate was filtered off and washed with 50% ether/ethyl acetate. The aqueous phase was also extracted with 50% ether/ethyl acetate and the combined solvent solution was washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent solution left 17 g of a solid which was passed through a silica gel column packed in hexane and eluted with 50% ether/hexane. The resultant solid was recrystallized from ether/hexane to give 15 g of a solid, m.p. 121°-123° C.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].CCN(CC)CC.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([O:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a CH2Cl2 (300 mL) solution of triethylene glycol (21 g, 140 mmol) was added Et3N (20 mL, 140 mmol); then trityl chloride (19.5 g, 70 mmol) in CH2Cl2 (100 mL) was added dropwise at 0° C. The mixture was stirred overnight and quenched with H2O. The organic phase was washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using hexane/EtOAc as the eluent to afford compound 21 (21 g, 53.6 mmol, 77% yield) as a clear liquid: 1H NMR (500 MHz, CDCl3) δ 7.47-7.46 (m, 6H), 7.28 (t, J=7.0 Hz, 6H), 7.21 (t, J=7.0 Hz, 3H), 3.68 (s, 8H), 3.60 (br, 2H), 3.25 (br, 2H), 2.57 (br, 1H); 13C NMR (126 MHz, CDCl3) δ 144.2, 128.8, 127.9, 127.1, 86.8, 72.7, 71.0, 70.8, 70.7, 63.4, 61.9; MS (ESI) m/z 415 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:14]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(NC2CCCCC2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (3-amino-phenyl)-tert-butoxycarbonylamino-acetic acid methyl ester (165 mg, CAS 180081-34-9) in MeOH (5 ml) was treated under an argon atmosphere with cyclohexanone (0.07 ml), zinc chloride (321 mg) and NaBH3CN (111 mg) and stirred overnight at 40° C. The MeOH was distilled off. The residue was taken up in EtOAc and H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with water, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane ->cyclohexane/EtOAc 14:1) to give (RS)-tert-butoxycarbonylamino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (200 mg, 94%) as viscous colorless oil.
Reaction SMILES: [CH:1]1([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCC1CCCCCCCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC1CCCCCCCCCCC1
Temperature: 55 °C
Yield: 25.1 %

Procedure:
To a solution of 7.6 g (30 mmol) of methyl 3-cyclododecylpropanoate in 100 ml of methanol is added 2.4 g of sodium hydroxide. The mixture is heated to 55° C. and is maintained for 4 hours. The reaction mixture is diluted with water and is extracted with hexane. The aqueous phase is acidified with 1N hydrochloric acid and is extracted (2 times) with ethyl ether. The combined ethereal extracts are washed with 1N hydrochloric acid and are dried over magnesium sulfate. Filtration and evaporation gives 7.48 g of crude title compound. Recrystallization of a portion of the product from hexane gives 1.81 g of the title compound: m.p. 72°-74° C.; IR (KBr) 1715 cm-1 ; NMR (CDCl3) δ 1.34 (m, 23 H), 1.57 (q, 2 H, J=8 Hz), 2.36 (t, 2 H, J=8 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.C1(C)C=CC=CC=1>[O:25]1[CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(-c2cncnc2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 148.1, 60 mg, 0.134 mmol), pyrimidin-5-ylboronic acid (50 mg, 0.403 mmol), Pd(Ph3P)4 (12.43 mg, 10.76 μmol) and finely ground K3PO4 (143 mg, 0.672 mmol) were added to a MW vial and treated with toluene (672 μL). The vial was sealed, evacuated/purged with argon then the RM was stirred 110° C. for 16 h, diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 56.0 mg, 0.081 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Diol, from 15% to 20% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.00 min, m/z=446.3 [M+H]+, m/z=444.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.09-3.20 (m, 4H) 3.50-3.60 (m, 4H) 7.38 (d, J=8.28 Hz, 2H) 7.86 (d, J=9.16 Hz, 2H) 8.23 (d, J=2.38 Hz, 1H) 8.84 (d, J=2.38 Hz, 1H) 9.13 (s, 2H) 9.22 (s, 1H) 10.37 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCNCCO
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCNCCO)cc1
Temperature: 60 °C
Yield: 92.7 %

Procedure:
6 g of 4-fluoronitrobenzene and 10 g of 2-(2-aminoethylamino)ethanol were added to a solution of 100 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 4 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 8.88 g of 2-[2-(4-nitrophenylamino)ethylamino]ethanol (1) were obtained.
Reaction SMILES: ClC(OCC)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[O:17][C:18]=2[CH2:19][CH2:20][C:21](O)=[O:22])=[CH:10][CH:9]=1.[NH3:30]>O.O1CCCC1.C(N(CC)CC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[O:17][C:18]=2[CH2:19][CH2:20][C:21]([NH2:30])=[O:22])=[CH:10][CH:9]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(N)=O)o1
Reaction time: 0.67 h
Yield: 90 %

Procedure:
Ethyl chloroformate (395 mg) was dropwise added to a tetrahydrofuran (40 ml) solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid (1.00 g) and triethylamine (365 mg), at +30° C. After stirring for 40 minutes, the reaction mixture was added to a mixture of aqueous ammonia (28%, 30 ml) and tetrahydrofuran (10 ml) at 0° C., and then stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide (900 mg, 90%). This was recrystallized from methanol-ethyl acetate to give colorless needles. mp 215-216° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[N:22]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([N:29]3[CH2:28][CH2:27][CH:26]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[CH2:31][CH2:30]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Reactant: c1cn(C2CCNCC2)nn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(N2CCC(n3ccnn3)CC2)ncc1F
Yield: 34.3 %

Procedure:
A solution of the product of Step 1 (123 mg, 0.42 mmol), 4-(1H-1,2,3-triazol-1-yl)piperidine (94 mg, 0.50 mmol) and diisopropylethylamine (2 mL) was irradiated in 2-propanol (2 mL), in a microwave oven, at 150° C. for 2 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (0%-100%) to give the product (59 mg, 34%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18]>CN(C)C=O>[Br:1][C:2]1[C:7](=[O:18])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(Cl)cc(Br)c[n+]1[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate (3, 150 g, 534.8 mmol) in dimethylformamide (900 mL) at 0° C. was added trifluoroacetic anhydride (224.63 g, 1.07 mmol). The temperature of the reaction mixture was raised to 50° C. and stirring was continued for 1 h. After the oxidation was complete, the reaction mass was quenched with a saturated aqueous sodium bicarbonate solution and product was extracted with dichloromethane (2×100 mL). The organic layers were separated, combined, dried with magnesium sulfate and concentrated to dryness under vacuum to afford ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow solid. Yield: 75 g, 50%; MS (ESI) m/z 281.8 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.44-10.02 (m, 1H), 7.86 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=5.6 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]#[C:4][CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].N1C2C(=CC=CC=2)C=CC=1.S([O-])([O-])(=O)=O.[Ba+2].[H][H]>C(OCC)(=O)C>[OH:1][CH:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]=[CH:4][CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCCCCC(O)C#CCCC(=O)CC(=O)OCC
Reactant: [H][H]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCCCCCC(O)C=CCCC(=O)CC(=O)OCC
Yield: 59.6 %

Procedure:
A solution of 10 g of the product of Step A in 50 ml of ethyl acetate containing 1 ml of quinoline was added to a suspension of 1 g of 50% palladized barium sulfate in 50 ml of ethyl acetate and the mixture was stirred in a hydrogen atmosphere until absorption ceased. The catalyst was removed by filtration and the filtrate was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica and was eluted with an 8-2 mixture of methylene chloride-ethyl acetate to obtain 6 g of ethyl 8-hydroxy-3-oxo-6-tetradecenoate in the form of a pale yellow oil with a refractive index of nD23 = 1.4602.