Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][C:17]([OH:19])=O.CN(C)C=O.[CH3:25][O:26][C:27]([C:29]1[C:34]([NH2:35])=[N:33][CH:32]=[CH:31][N:30]=1)=[O:28]>ClCCl.C(#N)C>[CH3:25][O:26][C:27]([C:29]1[C:34]([NH:35][C:17](=[O:19])[CH2:16][C:9]2[C:10]([F:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[Cl:7])=[N:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(O)Cc1c(F)ccc(F)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1nccnc1NC(=O)Cc1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 244.7 %

Procedure:
Oxalyl chloride (1.30 ml) was added dropwise to a solution of (2-chloro-3,6-difluoro-phenyl)-acetic acid (3.151 g) in dichloromethane (20 ml) and a drop of N,N-dimethylformamide was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated to produce a colourless oil which was dissolved in acetonitrile (30 ml). This solution was then divided into three portions and each portion was added to a slurry of 3-amino-pyrazine-2-carboxylic acid methyl ester (0.76 g) in acetonitrile (15 ml). The reaction mixtures were heated in the microwave at 130° C. for 40 minutes to produce dark red solutions that was stored at ambient temperature for 16 hours. The samples were combined and concentrated to produce 3-[2-(2-chloro-3,6-difluoro-phenyl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester as a dark orange solid (4.15 g). 1H-NMR (400 MHz, CDCl3): 4.02 (s, 3H), 4.22 (s, 2H), 7.02-7.10 (m, 1H), 7.11-7.17 (m, 1H), 8.41 (d, 1H), 8.61 (d, 1H), 10.8 (s, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1([C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]1)=[O:17])=[CH:10][CH:9]=2)([CH3:5])[CH3:4].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].O>ClCCl>[C:36]([NH:1][CH2:2][C:3]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1([C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]1)=[O:17])=[CH:10][CH:9]=2)([CH3:4])[CH3:5])(=[O:38])[CH3:37]
Reactant: CC(C)(CN)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (21 mg, 0.054 mmol) in dichloromethane (1 mL) was added pyridine (14 μL, 0.16 mmol) followed by acetic anhydride (6.0 μL, 0.059 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane, evaporated, coevaporated with toluene (3×) and purified by silica gel chromatography (60-100% ethylacetate in hexane) to give N-(2-(1-acetamido-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide (17 mg, 73%). 1H NMR (400 MHz, DMSO) δ 10.79 (s, 1H), 8.39 (s, 1H), 7.66 (t, J=6.2 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.18-7.14 (m, 1H), 7.02-6.89 (m, 4H), 6.08 (d, J=1.5 Hz, 1H), 6.03 (s, 2H), 3.31 (d, J=6.2 Hz, 2H), 1.80 (s, 3H), 1.41-1.38 (m, 2H), 1.26 (s, 6H), 1.04-1.01 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45](C#N)[CH2:44][N:43]6C(=O)C(NC(OC)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:66](=O)[NH:67]C(C(N1CC(C#N)CC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)C(C)C.C(OC(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)(C)(C)C.[CH3:130][N:131]([CH:133]([C:137]1[CH:142]=[CH:141][CH:140]=[CH:139][CH:138]=1)[C:134]([OH:136])=O)[CH3:132]>>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([C:66]#[N:67])[CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:134](=[O:136])[CH:133]([N:131]([CH3:130])[CH3:132])[C:137]6[CH:142]=[CH:141][CH:140]=[CH:139][CH:138]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: CN(C)C(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(c6ccccc6)N(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
Synthesized similar to [1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using [1-(4-Cyano-2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester and 2-[5-(4-Bromophenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester and dimethylamino-phenyl-acetic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.O>C1(C)C(C)=CC=CC=1>[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(O)c2ccccc2)cc1
Reactant: ClCCN1CCN(CC=Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(C(OCCN2CCN(CC=Cc3ccccc3)CC2)c2ccccc2)cc1

Procedure:
2 g of 60% sodium hydride in paraffin oil were added to a solution of 10 g (0.05 mol) of 4-methylbenzhydrol in 100 ml of anhydrous xylene. The reaction mixture was refluxed for half an hour and then 12.7 g (0.05 mol) of 1-(2-chloroethyl)-4-(3-phenyl-2-propenyl)piperazine (German pat.appl.2.431.178) in 50 ml of xylene were added dropwise. The reaction mixture was refluxed for another three hours and then cooled and poured into water. The organic layer was separated off, washed with water and concentrated. The residue was purified by column chromatography (Silicagel) with chloroform/ethylacetate/methanol/ammonia (25:25:1:0.5) as the eluent which yielded 1-[2-[(4-Methylphenyl)phenylmethoxy]ethyl]-4-(3-phenyl-2-propenyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:15])[S:5][C:6]=1[C:7]#[C:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:16](N1C=CN=C1)([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)=[O:17].C(N(CC)CC)C.CC(OC)(C)C>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:15][C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:17])[S:5][C:6]=1[C:7]#[C:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1C#Cc1cccnc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)n2ccnc2)sc1C#Cc1cccnc1
Yield: 91.7 %

Procedure:
As shown in step 2-iii of Scheme 2, compound 1004 (91 mg, 0.423 mmol), 1,1′-carbonyldiimidazole (103 mg, 0.634 mmol), and triethylamine (85.6 mg, 0.845 mmol) were stirred in 2.1 mL of DMF at 60° C. for 2 hours. After this time, MTBE was added and the resulting precipitate collected by filtration to produce N-(4-methyl-5-(pyridin-3-ylethynyl)thiazol-2-yl)-1H-imidazole-1-carboxamide (compound 1005, 120 mg), which was immediately used in subsequent reactions as is.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36].C(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:35][NH:36][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(Cl)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 3-(4-chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (260 mg, 0.56 mmol) and hydrazine monohydrate (3 mL) in methanol (20 mL) was stirred at 30° C. for 4 hr. The mixture was concentrated to give crude product, which was purified by prep-HPLC to give the title compound (34 mg, yield 14%) as a white solid of formic acid salt. LC-MS (ESI) m/z: 431 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.66 (s, 6H), 4.20-4.21 (d, J=4.8 Hz, 2H), 4.39-4.42 (d, J=8.8 Hz, 1H), 4.82-4.84 (d, J=8.8 Hz, 1H), 7.15-7.20 (m, 4H), 7.25-7.27 (d, 2H), 7.35-7.42 (m, 5H), 7.46 (s, 1H), 7.58-7.62 (t, J=8.0 Hz, 1H), 9.74 (br s, 1H), 12.18 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][C:52]([CH3:55])=[CH:53][N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][C:52]([CH3:55])=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1cnc(N)s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-methylthiazole (104 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-thiazol-2-yl)-propionamide (201 mg, 78%) as a orange foam: [α]23589=−72.7° (c=0.055, chloroform); EI-HRMS m/e calcd for C19H23ClN2O3S2(M+) 426.0838, found 426.0837.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[NH:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[NH:39]1[CH2:42][CH:41]([C:43]([N:23]2[CH2:22][CH:21]=[C:20]([C:18]3[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]4[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])=[O:13])[C:15]4[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=4[N:17]=3)[CH2:25][CH2:24]2)=[O:44])[CH2:40]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: O=C(O)C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to it Et3N (3 equiv.) and azetidine-3-carboxylic acid (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (81.9% yield). LCMS: 504.25 (M+1)+; HPLC: 99.74% (@ 254 nm) (Rt;4.829); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 8.84 (m, 2H), 8.64 (bs, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 6.93 (s, 1H), 5.89 (s, 1H), 5.22-5.17 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 4.26 (bs, 1H), 4.20-4.10 (m, 4H), 4.05-3.97 (m, 1H), 3.75 (t, 1H, J=5.2 Hz), 3.49 (m, 2H), 2.74 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.51 (d, 6H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[H-].[Na+].Cl>CN(C)C=O>[CH2:13]([O:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 90.3 %

Procedure:
1.83 g of 4-Chloro-3-nitrobenzonitrile and 1.06 g of neopentyl alcohol were dissolved in 10 ml of N,N-dimethylformamide. The solution was cooled to 0° C., and 480 mg of sodium hydride (60% in oil) was gradually added thereto. Then, 30 min after the addition, 13 ml of 1N hydrochloric acid was added to the mixture, and the precipitated crystal was collected by filtration to give 2.12 g of 4-neopentyloxy-3-nitrobenzonitrile. 1.2 g of thioacetamide was added thereto, and the mixture was heated at 80° C. for an hour in N,N-dimethylformamide saturated with hydrochloric acid. After the completion of the reaction, the reaction mixture was neutralized with 30 ml of water and 18 ml of 2N sodium hydroxide, and the lower layer was separated and dried. The lower layer was dissolved in 30 ml of ethanol, 2.11 g of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated under reflux for 5 hours. After the reaction mixture was cooled, the precipitated crystal was collected by filtration and recrystallized from ethanol to give 2.38 g of ethyl 4-methyl-2-(4-neopentyloxy-3-nitrophenyl)-5-thiazolecarboxylate (yield: 63%). This product was hydrolyzed by a conventional process, and the resulting crystal was recrystallized from a 80% aqueous ethanol solution to give 1.98 g of 2-(4-neopentyloxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid (yield:
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[CH2:23].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:2]([N:9]1[C@@H:14]2[C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH2:23][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (Description 1; 4.91 g, 14.3 mmol), phenyl vinyl sulphone (4.2 g, 25 mmol), triethylamine (2.8 ml, 20 mmol) and 1,4-dioxane (50 ml) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHCO3 and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 10-70%) to give the title compound (4.84 g, 78%) as a yellow-orange foam. Crystallisation from iso-hexane:diethyl ether gave the title compound as yellow rhombs.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=5)[N:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](N)C2)nc1
Yield: 69 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl 1-(5-(3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.16 mmol) was reacted with TFA (2.0 mL) to afford the desired product (56 mg, 67%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.27 (s, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.59 (dd, J=9.1, 2.8 Hz, 1H), 7.44 (s, 1H), 7.20 (d, J=11.7 Hz, 1H), 6.97 (d, J=9.1 Hz, 1H), 4.39 (dd, J=12.6, 3.4 Hz, 1H), 3.38-3.94 (m, 2H), 3.43-3.21 (m, 5H), 2.79 (s, 3H), 2.17 (m, 2H), 1.93 (m, 1H), 1.80-1.66 (m, 2H); ESI MS m/z 507 [M+H]+; HPLC 98.8% (AUC), tR=9.34 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([CH:12]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][NH:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:11]>[Hg]>[CH2:21]([CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][N:14]([CH2:13][CH:12]([CH2:10][CH3:11])[CH2:23][CH2:24][CH2:25][CH3:26])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH3:22]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: O=C(O)c1cnccn1
Agent: [Hg]
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)c1cnccn1

Procedure:
N,N-bis(2'-ethylhexyl)pyrazine-2-carboxamide was prepared from pyrazine-2-carboxylic acid and bis(2-ethylhexyl)amine by the general method of Example 5, the amine being used in place of the alcohol. The compound had a boiling range of 155° to 160° C. at 0.2 mm pressure of mercury.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:9])=[O:8])[CH:3]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>O1CCOCC1>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4cc(C)on4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
A solution of 5-methylisoxazole-3-carbonyl chloride (0.41 g., 2.83 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.82 g., 2.83 mmole) in dioxane. The mixture was treated as described in the previous example to give the title compound having a m.p. of 271°-273° C. with decomposition.
Reaction SMILES: [C:1]1([C@@H](N)C)[CH:6]=CC=[CH:3][CH:2]=1.[CH:10]1([CH2:16][NH:17][CH2:18][C:19]([N:21]2[CH2:26]COC[CH2:22]2)=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:26][N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][CH2:16][C:10]1[C:11]2[C:12](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CNCC1CCCCC1)N1CCOCC1
Reactant: C[C@H](N)c1ccccc1
Product: CN(C)C(=O)CNCc1cccc2ccccc12

Procedure:
By following the procedure of section (a) of this example but replacing (S)-1-phenylethylamine with twice the equivalent amount of 1-(naphthylmethyl)amine and omitting the triethylamine, N,N-dimethyl-2-[(1-naphthylmethyl)-amino]acetamide [1H NMR(CDCl3) δ 8.25 (dd, J=1.2 Hz,8.0 Hz,1H), 7.86 (dd, J=1.8 Hz,7.6 Hz,1H), 7.79 (broad d, J=8.1 Hz,1H), 7.60-7.39 (m,4H), 4.30 (s,2H), 3.52 (s,2H), 2.97 (s,3H), 2.90 (s,3H)] was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(N)cn2)C1
Yield: 37.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl 3-aminopiperidine-1-carboxylate (695 mg, 3.5 mmol) followed by reduction to afford the desired product (337 mg, 35%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc[n+]([O-])c(C)c1
Product: COc1ccnc(COC(C)=O)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To 2-methyl-4-methoxypyridine-N-oxide (23 g, 0.165 mole) in a 1 liter wide necked flask fitted with a large condenser was added ice-cool acetic anhydride (35 ml, 0.37 mole) with stirring. The mixture was allowed to warm to room temperature whereupon a vigorous exothermic reaction occurred. The dark mixture was stirred for 1 hour before evaporating the excess acetic anhydride and distilling the residue to give the title compound (23.26 g, 78%), b.p. 125° C. at 0.1 mm mercury.