Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](Cl)[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[C:24]([CH3:26])[CH:25]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(Cc2cc(C)nc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1(Cc2ccnc(C)c2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of ethyl N-tert-butoxycarbonyl-4-(2-chloro-6-methylpyridin-4-ylmethyl)piperidine-4-carboxylate (0.32 g, 0.81 mmol) and 5% palladium on charcoal (60 mg) in methanol (10 mL) was stirred under a balloon of hydrogen gas at room temp. for 3 h. The resultant mixture was filtered through a plug of Celite. The filtrate was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[F:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=O)=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:15]([C:14]2[CH:22]=[CH:23][C:11]([F:10])=[CH:12][CH:13]=2)[CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNC1
Agent: Cl
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCNC2)cc1

Procedure:
The title compound is prepared from 4-fluoroaniline and 3-(4-fluorobenzoyl)pyrrolidine hydrochloride according to the procedure of Example 31.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:15])[C@@H:7]([OH:14])[C@@H:8]([NH2:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4].[N:16]1([C:22]([NH:24][C:25]2([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[OH:14][C@@H:7]([C@@H:8]([NH:13][C:31]([C:25]1([NH:24][C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)=[O:32])[CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:15]
Reactant: CCCCNC(=O)[C@@H](O)[C@@H](N)CCCC
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCNC(=O)[C@@H](O)[C@H](CCCC)NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
In anhydrous dichloromethane were dissolved 254 mg (1.21 mmol) of (2S,3S)-N-butyl-3-amino-2-hydroxyheptanamide, 310 mg (1.21 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 230 mg (1.45 mmol) of 1-hydroxy-benzotriazole, subsequently, under nitrogen stream, 278 mg (1.45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to the solution at 0° C. Thereafter, the temperature of the reaction mixture was returned to room temperature and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 80 ml of ethyl acetate, and the resulting mixture was washed successively with water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 489 mg (Yield: 89%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:18])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=[O:25])[CH:20]=1>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][C:24]([N:21]2[CH:20]=[CH:19][N:23]=[CH:22]2)=[O:25])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1
Reactant: Cc1nc(N)sc1-c1ccc(-n2cccn2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(-n2cccn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-ylamine (1.5 g, 5.85 mmol) in dry DCM is treated with CDI (1.1 g, 7.02 mmol) followed by TEA (1.2 ml, 8.77 mmol). The resulting orange suspension is heated to reflux for 3 hours and then allowed to cool to room temperature overnight. The suspension is filtered and washed with DCM to afford the title compound. [MH+ 315.35].
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH3:22][N:23]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.[F-].[Cs+].C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([CH2:33][N:23]([CH3:22])[CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[CH:35][CH:36]=3)[S:10][C:9]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: CN1CCN(CCN(C)Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(CCN(C)Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)CC1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a mixture of the nitro compound 50 (440 mg, 1.19 mmol) in DME (20 ml) was added the boronate 75 (667 mg, 1.5 eq, 1.79 mmol), CsF (542 mg, 3 eq, 3.57 mmol) and Pd(PPh3)4 (139 mg, 0.1 eq, 0.19 mmol) were suspended in DME (30 ml) and NaHCO3 (100 mg, 3 eq, 3.57 mmol), dissolved in the minimum amount of water, was added. The mixture was deaerated by bubbling N2 through the solution for 10 min, heated to reflux for 4 hrs. The mixture was cooled to room temperature, diluted with EtOAc and water then the organic phase was collected, dried over sodium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography (20% MeOH in EtOAc+1% TEA) to afford title compound 79 as brown oil (248 mg, 39% yield). MS (m/z): 536.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:32])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[C:6]=1[Cl:7]>[Pd].CO>[Cl:1][C:2]1[N:3]=[C:4]([CH3:32])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=3)[CH2:16][CH2:17]2)[C:6]=1[Cl:7]
Reactant: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(OCc3ccccc3)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(O)cn2)CC1
Temperature: 24 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
A mixture of 2.90 g (6.10 mmol) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl )butyl]-1-piperazinyl}-5-benzyloxypyrimidine and 0.30 g of 10% palladium on carbon in 50 ml of methanol is stirred for 12 hours under a hydrogen atmosphere at room temperature (24° C.) and at a pressure of 0.28 MPa. After filtration, washing with methanol and evaporation to dryness, the product is chromatographed on silica gel, yielding 1.39 g (59%) of 2-{4-[4-(4,5-dichloro-2-methylimidazol -1-yl)butyl]-1-piperazinyl}-5-hydroxypyrimidine with a melting point of 154°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([C:21]#[N:22])[CH:3]=1.[H][H]>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[C:4]([C:21]#[N:22])[CH:3]=1
Reactant: [H][H]
Reactant: N#Cc1cc(Cl)ccc1-c1ccc(C(O)/C=C/C(=O)O)cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)ccc1-c1ccc(C(O)CCC(=O)O)cc1

Procedure:
9.90 gm (0.0316 mol) of 4-(4'-chloro-2'-cyano-4-biphenylyl)-4-hydroxy-crotonic acid in 500 ml of dry ethyl acetate were hydrogenated in the presence of 2.50 gm of Raney nickel, at a hydrogen pressure of 5 atmospheres and at room temperature until the end of hydrogen absorption. After filtering, the filtrate was washed twice with 100 ml of 1% hydrochloric acid each and then with water, dried over sodium sulfate and evaporated in vacuo. The oily, yellowish residue was dissolved in ethyl acetate and converted into the cyclohexylamine salt by addition of the equimolar quantity of cyclohexylamine. Yield: 6.15 gm; m.p. 168°-169° C. (from acetone/ethyl acetate 1:1).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([NH2:20])[C:16]([O:18][CH3:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)(=[O:4])=[O:3].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])[C:25]([F:44])=[CH:24][N:23]=1>>[F:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])=[N:27][C:22]([NH:20][C:15]2[C:16]([O:18][CH3:19])=[CH:17][C:10]3[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:23][CH:24]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1F
Reactant: COc1cc2c(cc1N)CCN(CCS(C)(=O)=O)CC2
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CCS(C)(=O)=O)CC2

Procedure:
The title compound was prepared from 3-(2-Methanesulfonyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2-Chloro-5-fluoro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.029 g, 25%). MP: 90-127° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.25 (d, 1H, J=8.8 Hz), 8.14 (s, 1H), 7.92-7.90 (m, 1H), 7.39 (s, 1H), 7.18 (d, 1H, J=1.8 Hz), 6.63 (s, 1H), 6.57 (d, 1H, J=1.8 Hz), 6.53 (dd, 1H, J=9.0 Hz and 1.9 Hz), 3.91 (s, 3H), 3.86 (s, 3H), 3.23-3.14 (m, 6H), 3.07 (s, 3H), 3.02 (t, 2H, J=6.3 Hz), 2.88-2.81 (m, 4H), 2.72-2.66 (m, 4H), 2.65-2.59 (m, 4H), 2.38 (s, 3H). MS: 614.27 (MH)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=2[O:2]1.[Mg].[B:12]([O:23]CCCC)([O:18]CCCC)[O:13]CCCC>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:13][B:12]([OH:23])[OH:18])=[CH:4][C:3]=2[O:2]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)Oc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of 3,4-methylenedioxybromobenzene (2.00 g, 9.95 mmol) in anhydrous THF (20 ml) was added dropwise to magnesium turnings(254 mg, 10.45 mmol) and stirred for 1 h. After the reaction completed, the reaction mixture was cooled to −78° C., and a solution of tributyl borate (3.22 ml, 11.94 mmol) in anhydrous THF (30 ml) was added dropwise and stirred for 15 min at the same temperature. Cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred for another 15 min. Ice water was added and the mixture was acidified with hydrochloric acid and extracted twice with ether. A combined organic layers were washed with brine and dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was air-dried to give 3,4-methylenedioxyphenyl boric acid (986 mg, 60%) as white crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:21][C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][NH:28]4)=[CH:24][CH:23]=3)[CH:11]=2)[C:6]([CH3:33])([CH3:32])[CH2:5]1)(=O)C.Cl>CCO>[CH3:32][C:6]1([CH3:33])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:21][C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][NH:28]4)=[CH:24][CH:23]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)ccc21

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide (500 mg) was deprotected heating with 12 N HCl (3 ml) and EtOH (3 ML) at reflux for 1 h. Dried under vacuum and purified via HPLC. M+H 399.3; Calc'd for C23H22N6O: 398.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)=[O:17]
Reactant: O=C(Cl)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1cnc2cc(C(F)(F)F)ccc2c1O
Yield: 56.6 %

Procedure:
Using the procedure of Step B of Example 1, 3.7 g of the acid chloride of Step A and 1.35 g of 2-amino-thiazole were reacted to obtain 2.58 g of N-[2-thiazolyl]-4-hydroxy- 7-trifluoromethyl-3-quinoline-carboxamide melting above 369° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].CN(C)C1C=CN=CN=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:20]([O:8][C:7]1[C:6]([Cl:9])=[N:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][C:2]=1[Cl:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1c(Cl)nc(-c2ccccc2)nc1Cl
Agent: CN(C)C
Agent: CN(C)c1ccncn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(Cl)nc(-c2ccccc2)nc1Cl

Procedure:
A solution of 3.1 g of 4,6-dichloro-5-hydroxy-2-phenylpyrimidine, 2.8 ml of trimethylamine, 1.6 ml of acetic anhydride and 0.1 g of 4-dimethylaminopyrimidine in 50 ml of toluene is stirred for 4 hours at 20°-25° C. The reaction solution is subsequently diluted with ethyl acetate, washed with water and dried. On concentration by evaporation, there crystallise 4.3 g of 5-acetoxy-4,6-dichloro-2-phenylpyrimidine, m.p. 145°-147° C. (compoud No. 36).
Reaction SMILES: [NH3:1].[I:2][C:3]1[C:8]2[N:9]=[C:10]([CH3:14])[O:11][C:12](=O)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:15]>CCOC(C)=O>[I:2][C:3]1[C:4]([CH3:15])=[CH:5][CH:6]=[C:7]2[C:8]=1[N:9]=[C:10]([CH3:14])[NH:1][C:12]2=[O:11]
Reactant: Cc1nc2c(I)c(C)ccc2c(=O)o1
Reactant: N
Solvent: CCOC(C)=O
Product: Cc1nc2c(I)c(C)ccc2c(=O)[nH]1
Temperature: -78 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Anhydrous ammonia (50 mL) was condensed in a 500 mL 3 necked flasked containing 8-iodo-2,7-dimethyl-4H-benzo[d][1,3]oxazin-4-one (8.5 g, 28 mmol) cooled to −78° C., and the reaction was stirred for 3 h. The cooling bath was removed and the solvent was allowed to evaporate at RT. 1 N Sodium hydroxide (100 mL) was added to the reaction and stirred at reflux for 1 h. The reaction was cooled down to 0° C. and acidified to pH 3 with 5 N HCl. The resulting precipitate was collected by filtration, washed with water and dried in a vacuum oven at 60° C. overnight. 8-Iodo-2,7-dimethylquinazolin-4(3H)-one (8 g, 94% yield) was obtained as a white solid. MS (M+H)+ 301.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)(C)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: C#Cc1cccc(N)c1
Yield: 82 %

Procedure:
Example 6 was repeated using 50 grams of 3-nitrophenylacetylene (19% wt. conc.) in isopropanol in the presence of 8.0 grams of said cobalt polysulfide catalyst (weight ratio of NPA to Co of 50:1) for 1.1 hours at 120° C. and 1000 psig (6.9 MPa) of hydrogen pressure. Analysis showed quantitative conversion and 82% yield of 3-aminophenylacetylene. All byproducts were polymeric. The results are summarized in Table 1 below.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)O)=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:31])=[C:24]([Cl:23])[CH:25]=1)[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:4]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cn1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(Cl)cn1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 5-bromo-2-[(5-chloro-pyridin-2-yl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BK2) and 3-chloro-4-fluoroaniline [367-21-5] were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a beige foam. ESI-MS: tR=1.51 min, [M+H]+ 514/516/518 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][OH:15])[CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: OCCCN1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
3,6-dichloropyridazine (14.90 g, 100 mmol), sodium carbonate (10.60 g, 100 mmol) and DMA (80 mL) were placed in a 250 mL three-necked bottle, and the solution of 1-(3-hydroxypropyl)piperazine (14.4 g, 100 mmol) in DMA (20 mL) was added slowly in dropwise within 30 min under an ice-bath condition. The mixture was stirred at room temperature overnight, distilled under a reduced pressure to remove the solvent to obtain a brown solid, which was subjected to a column chromatography (gradient elution: petroleum/acetone system, v/v 2: 1 to acetone) to obtain a white solid, 13 g, yield 50.8%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19](CC)CC)[CH3:18].C(Cl)(=O)OCC.C(N)C>O.O1CCCC1>[CH2:17]([NH:19][C:14](=[O:16])/[CH:13]=[CH:12]/[C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.76 g), triethylamine (0.8 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.4 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ethylamine solution (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give (E)-N-ethyl-3-(5-phenyl-4-isoxazolyl)propenamide (0.78 g, yield 91%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 156–157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2n(C2CCCCC2)c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
26.3 g (94 mmol) of 6-chloro-1-cyclohexylquinoxaline -2,3(1H,4H)-dione were dissolved in 275 ml of concentrated sulfuric acid and subsequently, at 0° C., 9.5 g (94 mmol) of potassium nitrate were added in portions. The mixture was then stirred at 0° C. for 30 min and at 25° C. for 2 h and subsequently poured into ice-water, and the precipitate was filtered off with suction. 29.5 g (97%) of the product were obtained. Melting point >300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3ccccn3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3ccccn3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyridin-2-yloxy)biphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (70 mg, 0.34 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol), and N,N-diisopropylethylamine (400 μL, 2.30 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)CCC>[N:1]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Nc1cccc2cc[nH]c12
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1cc(N2CCNCC2)c2[nH]ccc2c1
Yield: 32.3 %

Procedure:
A suspension of 7-aminoindole (4.10 g, 0.031 moles), bischloroethylamine hydrochloride (6.23 g, 0.035 moles) and potassium carbonate (9.66 g, 0.035 moles) in butanol (100 ml) was heated at reflux under argon for 6h. Further bischloroethylamine hydrochloride (3.0 g, 0.016 moles) and potassium carbonate (4.5 g, 0.016 moles) was added, then the suspension was heated at reflux under argon for 18 h. The solvent was evaporated in vacuo to give a deep purple residue which was taken up into dilute hydrochloric acid (300 ml), washed with ethyl acetate (2×100 ml), made basic with sodium hydroxide, extracted into dichloromethane, filtered, dried (MgSO4) then evaporated in vacuo to a yellow oil. This was crystallised twice from ether to give 7-(1-piperazinyl)indole (2.07 g, 0.010 moles) as a grey/white solid.