Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>CN(C=O)C>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=3)=[O:32])[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5ccc(F)cc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) in DMF (1 ml) was added p-tolyl isocyanate (21 μl, 0.17 mmol) in DMF (0.3 ml). The reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4. After removing the solvents in vacuo, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (31 mg, 44%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[O:46][C:45]([C:47]2[CH:48]=[C:49]([S:53](Cl)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=2)=[N:44][N:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:53]([C:49]2[CH:50]=[CH:51][CH:52]=[C:47]([C:45]3[O:46][C:42]([CH3:41])=[N:43][N:44]=3)[CH:48]=2)(=[O:55])=[O:54])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1nnc(-c2cccc(S(=O)(=O)Cl)c2)o1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc(-c2cccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)c(F)c3-c3cccnc3F)c2)o1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 18 mg) in tetrahydrofuran (0.5 mL) were added dropwise a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (97 mg) in tetrahydrofuran (0.5 mL), 15-crown-5 (100 mg) and 3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl chloride (85 mg) under ice-cooling and the mixture was stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 85 mg, 52%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)=[CH:26][N:25]=2)=[CH:20][CH:19]=1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[C:44]([C:48]1[S:52][C:51]([C:53](O)=[O:54])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[C:44]([C:48]1[S:52][C:51]([C:53]([NH:1][C@@H:2]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=4)=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][C@H:6]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4])=[O:54])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Prepared using General Procedure 7: A stirred solution of (S)-tert-butyl 1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (306 mg, 0.522 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (106 mg, 0.574 mmol) in DMF (6 mL) was added TEA (145 μl, 1.043 mmol), cooled to 0° C., then HATU (218 mg, 0.574 mmol) was slowly added over 5 minutes. The reaction was stirred at room temperature for 2 h, then diluted with EA (70 mL), washed with saturated aqueous NaHCO3 (70 mL) and brine (100 mL). The solvent was dried over MgSO4 and removed. The crude product was purified by chromatography 0-30% ACN in DCM to afford 363 mg (92%) of (S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)pyrrolidine-2-carboxylate as a sticky solid. LCMS-ESI (m/z) calculated for C44H56N4O5S: 752.4; no m/z observed, tR=11.99 min (Method 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:26].[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[C:49]2([OH:55])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][C:49]([C:41]3[N:40]([CH2:39][C:38]4[CH:56]=[CH:57][C:35]([F:34])=[CH:36][CH:37]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)([OH:55])[CH2:50][CH2:51]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:8]1=[O:26]
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(4-fluoro-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[l-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.38 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[C:17]([CH2:24]I)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1.O>CN(C)C=O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH2:24][C:17]1[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=2)[N:18]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cn2ccccc2=O)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Oily sodium hydride (60%, 0.117 g) was added to a solution of 2-hydroxypyridine (0.277 g) in N,N-dimethylformamide (DMF)(10 ml), and the mixture was stirred at room temperature for 15 minutes. To this solution was added ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylate (1.2 g). The mixture was stirred at room temperature for 8 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (10/1, v/v) gave ethyl 2-(1,2-dihydro-2-oxopyridine-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.64 g, 57%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-156° C.
Reaction SMILES: [Mg:1].[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].C([Cl:15])CCC>>[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[CH2:2]([Mg:1][Cl:15])[CH2:3][CH2:4][CH3:5]
Reactant: [Mg]
Reactant: CCCCCl
Solvent: CCCCOCCCC
Product: CCCC[Mg]Cl
Reaction time: 5 h

Procedure:
To a 1-liter flask equipped with a stirrer, a reflux condenser and a dropping funnel was added magnesium chip (12 g) for Grignard reagent. After replacing atmosphere in the flask by argon, di-n-butyl ether (250 ml) was added, and then n-butyl chloride (62 ml, 1.2 times by mole based on magnesium) was added dropwise to start reaction with the contents of the falsk kept at 50° C. After addition over 2 hours at 50° C., reaction was continued at this temperature for further 5 hours to obtain a di-n-butyl ether solution of n-butylmagnesium chloride. The concentration of this solution was 1.45 mole/liter.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1ccsc1Br
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: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1ccsc1-c1ccc(S(C)(=O)=O)cc1

Procedure:
Intermediate B (2.30 g, 9.78 mmol), 4-methylsulfonylphenylboronic acid (1.96 g, 9.78 mmol), K2CO3 (4.15 g, 30.0 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.130 mmol), MeCN (30 ml) and water (10 ml) were heated at 70° C. for 1 hour. The organic phase was removed in vacuo and the crude material was dissolved in DCM. The mixture was purified by flash chromatography using 30% and 50% EtOAc in iso-hexane as eluent. Yield: 2.25 g (74%); white solid. 1H NMR (400 MHz, CDCl3): δ 3.11 (s, 3H), 3.67 (s, 2H), 3.74 (s, 3H), 7.13 (d, J 5.0 Hz, 1H), 7.39 (d, J 5.0 Hz, 1H), 7.67-7.72 (m, 2H), 7.98-8.04 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[S:9][C:5]=2[CH:4]=1.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[N+:18]([C:17]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2nc(-c3ccccn3)sc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2sc(-c3ccccn3)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxy -2-(pyridinyl)benzothiazole, 30 g, (0.124 mole) is dissolved in 115 cc of concentrated H2SO4 and cooled to 0°. Nitric acid, 7.9 cc (0.124 mole) is added and the solution stirred for 2 hours at room temperature. The reaction mixture is poured on ice and the pH adjusted to 10 with 50% NaOH solution. The precipitate is filtered and dried to yield 11 g of product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH3:28][C:25]([CH3:29])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]#[N:27]
Reactant: CC(C)(C#N)CCCCBr
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridinone (6.3 g), 6-bromo-2,2-dimethylhexanonitrile (2.60 g) (prepared according to the method of M. Larcheveque et al., Bull. Soc. Chim. Fr., 1710 (1974)), silver carbonate (3.5 g) and toluene (300 cc). The product is purified by chromatography under pressure on silica gel (30-60 mm); eluent: n-hexane-ethyl acetate 9.5-0.5),yellowish solid. (m,p.=71° C.)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([F:29])=[CH:21][CH:20]=2)[C:8]=1[F:33])(=[O:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([F:33])=[C:9]([NH:16][C:17](=[O:32])[C:18]([F:30])([F:31])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([F:29])=[CH:21][CH:20]=2)[CH:10]=[CH:11][C:12]=1[NH2:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)OCCc1c(N)ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 5 h
Yield: 83.3 %

Procedure:
A mixture of 2-{3-[2,2-difluoro-2-(4-fluoronaphthyl)acetylamino]-2-fluoro-6-nitrophenyl}ethyl acetate (4.9 g, 10.5 mmol), as prepared in the preceding step, and Pd/C (10%, 500 mg) in ethanol (50 mL) and THF (50 mL) was stirred under hydrogen for 5 hours. The reaction mixture was filtered through Celite, and washed with THF and MeOH. The filtrate and washings were combined, concentrated in vacuo, and flash chromatographed on silica gel eluting with EtOAc/DCM (0 to 2%) to produce the title compound (3.8 g, 83%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.10 (s, 1H), 7.82 (m, 2H), 7.63 (m, 2H), 7.19 (t, J=8.6 Hz, 1H), 6.46 (d, J=8.7 Hz, 1H), 4.19 (t, J=7.4 Hz, 2H), 4.08 (s, 2H), 2.91 (t, J=7.3 Hz, 2H), 2.08 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2[C:22](=[O:32])[NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=[CH:7][CH:8]=1)#N.C(O)=[O:34]>[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2[C:22](=[O:32])[NH:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:6]=[CH:7][CH:8]=1)=[O:34]
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1C(=O)NCCN1CCOCC1
Reactant: O=CO
Agent: [Ni]
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C=O)c2)c1C(=O)NCCN1CCOCC1

Procedure:
A mixture of 4-{3-cyanophenyl)-2-methyl-3-(2- morpholinoethylcarbamoyl)-6-phenylpyridine (1.5 g) and Raney's Nickel (1.5 g) in 75% formic acid (40 ml) was refluxed for one hour under stirring. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the resultant solution was adjusted to pH 8.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to a column chromatography on silica gel and eluted with a mixture of ethyl acetate and diisopropyl ether (8:2 V/V). The eluted solution was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 4-(3-formylphenyl)-2-methyl-3-(2-morpholinoethylcarbamoyl)-6-phenylpyridine (0.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:12]=1[C:13]([NH2:15])=[O:14].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:15][C:13](=[O:14])[C:12]2[C:11](=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[N:10]=1
Reactant: O=Cc1ccccc1Cl
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccc3Cl)nc2c1
Temperature: 140 °C
Yield: 38.9 %

Procedure:
A mixture of 2-chlorobenzaldehyde (0.0430 g, 306 mmol), 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), NaHSO3 (94%, 0.0474 g, 0.428 mmol), and p-TsOH.H2O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at 140° C. for 16 h. The mixture was cooled and chromatographed on silica gel, fractions containing the product were combined, concentrated under vacuum, diluted with EtOAc (300 mL), washed with water (3×75 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0377 g, 39%) as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.65-7.40 (m, 4H), 6.72 (d, J=2.29 Hz, 1H), 6.59 (d, J=2.30 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (APCI) m/z 317 [M+H]+.
Reaction SMILES: I[C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN(C)C=O>O>[C:17]([C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CN1CC(=O)Nc2cccc(I)c2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)Nc2cccc(C#N)c2C1=O

Procedure:
A mixture of 5.7 g (0.018 mol) of 3,4-dihydro-6-iodo-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione, 2.4 g (0.026 mol) of copper (I) cyanide and 60 ml of dimethylformamide is heated to 50° for 45 minutes. After cooling, the mixture is diluted with water and extracted several times with chloroform/isopropanol (4:1). The combined organic extracts are dried over magnesium sulphate and evaporated. The yellow-brown crude product is recrystallized from methanol, there being obtained 6-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 253°-256° (decomposition).
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH2:14][CH3:15])=[C:12](Cl)[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH2:14][CH3:15])=[C:12]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1CC
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CC
Yield: 209.4 %

Procedure:
A mixture of butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine (200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.963 g, 7.1 mmol) was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated potassium carbonate and brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of the dark oil which was then purified through silica gel column chromatography using chloroform as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.14 (t, 3H), 1.1–1.4 (m, 4H), 1.45–1.60 (m, 2H), 2.17 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2–3.4 (m, 4H), 6.90 (s, 2H) ppm.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][NH:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41]>CC(O)C>[Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.) in i-PrOH (0.09 M) was added DIEA (2.5 equiv.) and 4-chloro-3-nitropyridine (1.5 equiv.). The reaction mixture was stirred at 60° C. for 2 hours. The volatiles were removed under vacuo, the residue was diluted with ethyl acetate and washed with sat. NaCl. The organic phase was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:2) to give tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in 76% yield. LC/MS=467.3 (M+H), Rt=1.09 min.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([NH:32][N:33]2[NH:37][CH:36]=[CH:35][S:34]2)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([C:30](=[O:31])[NH:32][N:33]4[NH:37][CH:36]=[CH:35][S:34]4)[CH:38]=[CH:39][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.43 min, MH+ 528. NMR: δH [2H6]-DMSO 13.07,(1H, b), 11.74,(1H, s), 9.26,(1H, s), 9.21,(1H, s), 8.43,(1H, d), 8.34,(1H, d), 8.29,(1H, s), 8.12,(1H, d), 7.93,(1H, d), 7.56,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.78,(2H, s), 2.67-2.26,(11H, m), 2.11,(3H, s).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:23]=[CH:22][C:10]([C:11](=[O:21])[CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14]2)=[CH:9][CH:8]=1.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+]>O1CCCC1.O>[C:26]([CH:25]([CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:13]([CH2:12][C:11]([C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[O:21])[CH2:14]1)[C:24]([O:30][CH2:31][CH3:32])=[O:29])(=[O:27])[CH3:28]
Reactant: O=C(CC1CCN(CCO)C1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCN1CCC(CC(=O)c2ccc(F)cc2)C1)C(C)=O
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A solution of 3.88 g of methanesulfonyl chloride is added at 0° C. to a suspension of 8.5 g of the product obtained in Stage A in 100 ml of tetrahydrofuran. The mixture is left stirring for 3 hours at 15° C., and this suspension is then added to a solution, cooled to 0° C., of 4.4 g of ethyl acetoacetate containing 1.63 g of sodium hydride in 100 ml of tetrahydrofuran. The mixture is then brought to reflux for 12 hours, hydrolyzed with 5 ml of water and concentrated, and the residue is take up in 150 ml of dichloromethane. The organic phase is washed with 50 ml of water, dried over anhydrous sodium sulfate and concentrated. The oil obtained is purified by chromatography on 600 g of 70-230 mesh silica, using a mixture of dichloromethane and methanol (99:1 V/V) as eluant.