Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH:8]2[CH2:12]OS(=O)(=O)[N:9]2[CH:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([NH:41][CH2:12][CH:8]([NH:9][CH:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CC2COS(=O)(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(CC(CNCc2ccccc2)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
t-Butyl 2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3) oxathiazolidin-3-yl)-3-methylbutyrate (1.0 g; 2.5 mmol) was dissolved in acetonitrile (15 ml). Cs2CO3 (1.63 g; 5 mmol) and benzylamine (0.5 ml; 4.5 mmol) were added, The reaction mixture was stirred at 55° C. for 4 h. It was then allowed to reach RT, and the reaction mixture was filtered through a clarifying layer. The residue was washed with acetonitrile. The filtrate was concentrated and taken up in CH2Cl2 (10 ml). Aqueous H2SO4 (20%; 5 ml) was added, and the mixture was stirred at RT for 1.5 h. The phases were then separated, the aqueous phase was extracted with CH2Cl2 (2×), and the combined organic phases were dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was stirred with CH2Cl2/CH3CN/Et2O and concentrated. t-Butyl 2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate (1.15 g; 2.5 mmol) was obtained as a yellowish foam. MS: 427.20 (M+H); Rt: 1.42 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[N:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([Cl:42])[CH:38]=5)[CH:33]=4)(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([S:29]([N:26]1[CH2:25][CH2:24][N:23]([C:21]([C:18]3[N:19]=[N:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]4)=[CH:16][CH:17]=3)=[O:22])[CH2:28][CH2:27]1)(=[O:30])=[O:31])[CH:41]=[CH:40]2
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)nn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(N2CCCNCC2)nn1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 1-[6-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)pyridazin-3-ylcarbonyl]-4-(6-chloronaphthalen-2-ylsulfonyl)piperazine (0.320 g, 0.52 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred overnight at room temperature, and the solvent removed by evaporation. The residue was purified using a SCX column to afford the title product (0.230 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[CH:13][CH:12]=3)[O:8][C:7](=[O:23])[C:6]=2[CH:24]=1.O.[NH2:27][NH2:28].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[O:8])=[C:6]([C:7]([NH:27][NH2:28])=[O:23])[CH:24]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3ccnn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1ccnn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.50 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.13 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain 0.44 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc([C@@H]2CCCN2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@H]1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 120° C. and MS: m/e=339 (Me) was prepared in accordance with the general method of example 1e from (S)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:37][CH2:35][CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCN
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:5]1)[CH3:2].[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:3][CH:4]1[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([NH:14][C:28]([C:26]3[N:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:24][C:25]=3[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:12][CH:13]=2)[CH2:5]1)[CH3:2]
Reactant: CCOC1CN(c2ccc([N+](=O)[O-])cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC1CN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 69.2 %

Procedure:
2-(3-Ethoxy-azetidin-1-yl)-5-nitro-pyridine (59 mg, 0.264 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (74 mg, 0.29 mmol), Et3N (186 uL, 1.32 mmol) and BOP (122 mg. 0.277 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-ethoxy-azetidin-1-yl)-pyridin-3-yl]-amide as a solid (79 mg). ES-MS calcd for C21H19F3N4O3 (m/e) 432.41, obsd 433.1 (M+H).
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([NH:29]N)=[O:28])[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4].Cl.C(ON=O)(C)(C)C.N[C@H:47]([C:51]([NH:53][C@H:54]([C:62]([NH:64][C@H:65]([C:69]([NH:71][C@H:72]([C:77]([OH:79])=[O:78])[CH2:73][CH:74]([CH3:76])[CH3:75])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60])=[O:52])[C@@H:48]([CH3:50])[OH:49]>CN(C)C=O.O1CCOCC1.C(N(CC)CC)C>[NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([NH:29][C@H:47]([C:51]([NH:53][C@H:54]([C:62]([NH:64][C@H:65]([C:69]([NH:71][C@H:72]([C:77]([OH:79])=[O:78])[CH2:73][CH:74]([CH3:76])[CH3:75])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:28])[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4]
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)NN
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)NCSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C
Reaction time: 0.17 h

Procedure:
13.6 g of Boc-Ser-Asn-Leu-Ser-NHNH2 are dissolved in 150 ml of dimethylformamide, cooled to -20°, then 40 ml of an anhydrous solution of HCl (2N) in dioxane are added, followed by 3.6 ml of tert.-butylnitrite. After 10 minutes at -20°, 16 ml of triethylamine and 13.0 g of H-Thr-Cys(Acm)-Val-Leu-OH are added, and the solution stirred for 16 hours at 25°. The mixture is filtered, the filtrate is evaporated to dryness, the residue is suspended repeatedly in 1N acetic acid and in water, filtered and dried to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[S:13](=[O:16])(=[O:15])[NH2:14])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:19])=[O:9])=[CH:6][C:5]=1[S:13](=[O:16])(=[O:15])[NH2:14])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1S(N)(=O)=O
Product: CC(C)c1ccc(C(=O)Cl)cc1S(N)(=O)=O

Procedure:
5 g of 4-isopropyl-3-sulfamoylbenzoic acid were boiled under reflux in 50 ml of thionylchloride until completely dissolved and the reaction mixture was then concentrated to 25 ml under reduced pressure. After allowing to dwell over night at 0° C, the crystals were filtered off over a sinter glass frit and washed with petroleum ether. Colorless body, melting point: 177° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][CH2:6][C:7]1[N:8]=[C:9]([N:12]=[C:13]([NH2:15])[NH2:14])[S:10][CH:11]=1)#[N:2].Cl.[CH2:17]=[O:18]>>[NH2:15][C:13](=[N:12][C:9]1[S:10][CH:11]=[C:7]([CH2:6][S:5][CH2:4][CH2:3][C:1](=[NH:2])[O:18][CH3:17])[N:8]=1)[NH2:14]
Reactant: C=O
Reactant: N#CCCSCc1csc(N=C(N)N)n1
Agent: Cl
Product: COC(=N)CCSCc1csc(N=C(N)N)n1

Procedure:
reacting the compound produced in step (b) with hydrogen chloride and methanal to obtain the compound methyl 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]-methyl]thio]propionimidate isolating and drying said compound; and
Reaction SMILES: C([NH:8][CH:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([CH:9]([NH2:8])[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine and trifluoroacetic acid in dichloromethane.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[H-].[Na+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18].Cl.[OH-].[K+]>CN(C)C=O.CO.O.C(OCC)(=O)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc2ccccc2n1CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
1H-Indole-2-carboxylic acid ethyl ester(1.027 g, 5.4 mmol) was dissoved in 15 ml of dry dimethylformamide and stirred under nitrogen in an ice-bath. Sodium hydride (60% in paraffin oil; 274 mg, 6.85 mmol) was added and the solution stirred at room temperature for 1.5 hours. To the reaction mixture 2-(4-nitrophenyl)ethyl bromide (1.29 g, 5.6 mmol) was added and the solution was stirred overnight. The reaction mixture was heated for 4 hours at 60° C. After completion of the reaction (thin layer chromatography, chloroform/methanol/acetic acid 90:9:1) 20 ml of 2 N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate, and evaporated to give an orange-red oil. The oily product was taken up in methanol/water (15 ml), and 1.2 g of potassium hydroxide were added. The reaction mixture was stirred overnight to complete the hydrolysis. Workup was achieved by addition of 2 N hydrochloric acid and extraction with ethyl acetate. Washing of the ethyl acetate layer with water, drying with magnesium sulfate, and evaporation in vacuo gave 1(2-(4-nitrophenyl)-ethyl)-1H-indole-2-carboxylic acid. MS: 310.2.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH3:3].[CH3:12][O:13][N:14]=[CH:15][CH3:16].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:12][O:13][N:14]1[CH:15]([CH3:16])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11]
Reactant: CC=NOC
Reactant: C=C(C)C1CCCCCC1=O
Agent: CON1C(=O)CCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cycloheptanone (0.97 g, 6.38 mmol), acetaldehyde O-methyl oxime (0.56 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.29 g, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:32][C:33]1[C:38]([NH2:39])=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[NH2:32][C:33]1[C:38]([NH:39][C:14](=[O:16])[CH2:13][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:12])=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: Nc1cccnc1N
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC(=O)Nc1cccnc1N)C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 19.4 %

Procedure:
N-(Benzyloxycarbonyl)sarcosine (4.1 g, 18.5 mmol) was dissolved in dry THF, and triethylamine (3 mL, 21.6 mmol) was added, followed by isobutylchloroformate (2.5 mL, 19.27 mmol). The solution was cooled to about -20° C. for 15 minutes, then a solution of 2,3-diaminopyridine (2.0767 g, 19.03 mmol) in dry THF was added slowly. The reaction was kept stirring between -10° C. to -20° C. for 15 minutes, then was allowed to warm to RT. After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc and 1N NaHCO3. The EtOAc phase was dried (MgSO4) and evaporated under vacuum. The residue was dissolved in glacial AcOH and was stirred in a oil bath at 70° C. After 24 h, the reaction was removed from the oil bath, allowed to cool to RT, and concentrated under vacuum. The residue was evaporated with toluene, then was chromatographed on silica gel (CHCl3, then 3% MeOH/CHCl3, then 5% MeOH/CHCl3) to afford the title compound (1.13 g, 19%): 1H NMR (250 MHz, CDCl3) δ 3.05 (s, 3H), 3.99 (s, 2H), 4.82 (br s, 1H), 6.5-6.65 (m, 1H), 7.32 (s, 5H), 7.87 (d, 1H), 8.84 (br s, 1H); MS (ES) m/e 315.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N[C:10]1[C:11](C)=CC=C[CH:15]=1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]([CH3:11])[CH3:15])[C:3]=1[NH2:4]
Reactant: Nc1ccccc1F
Reactant: Cc1ccccc1N
Product: CC(C)c1cccc(F)c1N

Procedure:
The procedure of Example 6 was repeated, except that ortho-fluoroaniline was substituted for ortho-toluidine. An LHSV of 0.125 hr.-1 and an N/R ratio of amine to olefin was 1:3. Table 4 sets forth the reaction conditions and results.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.I[CH2:16][CH2:17][CH2:18][CH3:19]>[Cu]I.O1CCCC1>[CH2:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)CCCCc2ccc(Br)cc21
Reactant: CCCCI
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCc1ccc2c(c1)C(C)(C)CCCC2
Temperature: -15 °C

Procedure:
The corresponding Grignard compound was prepared under argon from 304 mg of Mg shavings and 2.50 g of 2-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene in 25 ml of abs. tetrahydrofuran. After cooling to -15° C. 206 mg of CuI and 1.78 ml of 1-iodobutane were added in succession. The mixture was left to react at room temperature for 2 hours and then poured into ice/ammonium chloride solution. The solution was extracted with diethyl ether, washed with water, dried and evaporated. After filtration over SiO2 with hexane as the eluent there were obtained 2.27 g of 2-butyl-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo-cycloheptene (contaminated with 4% regioisomers and 6% 5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocyloheptene).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].[C:6]([OH:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1>C1(C)C=CC=CC=1>[C:6]([O:14][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCCCO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1cccnc1
Temperature: 116 °C
Reaction time: 6 h

Procedure:
n-Butanol (177.6 g, 2.4 mol), nicotinic Acid (98.4 g, 0.8 mol) and toluene (45.0 g) were charged to a 450 ml pressure reactor kettle and equipped with mechanical stir, a pressure take-out trap, and a thermocouple. The reactor was sparged with nitrogen and heated to 116° C., sealed, then heated to 200° C. and held for 6 hours. The mixture was then removed from the reaction kettle and volatiles removed under vacuum on a rotary evaporator at 60° C. The product was then purified by combining it with 50.0 g toluene and 60.1 g 4.4% NaOH solution in a 500 mL separatory funnel. The organic layer was then separated, dried over 5 g MgSO4 and solvents removed under vacuum on a rotary evaporator at 60° C. to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:6]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH3:6]
Reactant: COC(=O)C(CC=C(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CCC(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine methyl ester (22.1 g, 81.44 mmol) in 400 ml of methanol under nitrogen was cooled to 0° C. and 1.5 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated at 50 psi for 6 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo to afford 22.04 g (99%) of N-t-butoxycarbonyl-2-(3-methylbutyl)-sarcosine methyl ester as an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=[O:15])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].[H-].[Na+].C(O)(=O)C>O>[CH:1]1([C:4]2[C:13]([CH:14]([OH:15])[CH2:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CC#N
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 0.20 g (0.68 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL of acetonitrile and 0.042 g (1.06 mmol) of sodium hydride (purity: 60w). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture was added 0.08 mL (1.40 mmol) of acetic acid, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, to the mixture was added 10 mL of chilled water, and the mixture was extracted with 20 mL of ethyl acetate which were previously chilled in an ice bath. The organic portion was washed successively with 5 mL of saturated aqueous sodium hydrogen carbonate solution and 5 mL of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The organic portion was then filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography [column Wakogel C-200, available from Wako Junyaku Co., Ltd., eluent: ethyl acetate/hexane (7/93→15/85, vol. ratio)] to give 0.17 g (yield 75%) of 3-[2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3-hydroxypropionitrile as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(Oc3ccc(F)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.0 grams (0.012 mole) of 3-fluoro-5-(4-fluorophenoxy)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0)in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-(4-fluorophenoxy)phenyl]pyridine.