Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=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>[NH2:1][C:2]1[CH2:3][C:4]([C:14](=[O:15])[N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: COC(=O)c1ccc(B(O)O)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: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OC)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 23 %

Procedure:
(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 20 mgs (23%) of methyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.08-8.13 (m, 2H), 7.68-7.74 (m, 2H), 7.52-7.56 (m, 1H), 7.33-7.39 (m, 2H), 6.84 (s, 1H), 3.94 (s, 3H), 3.60-3.68 (m, 2H), 3.37-3.51 (m, 4H), 2.86 (s, 2H), 1.60-1.72 (m, 4H), 0.88-0.98 (m, 6H); m/z (APCI-pos) M+1=420.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:16][CH:17]=2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using 5-(methylsulfonyl)-1H-indole (intermediate-21) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate-29) (0.188 g, 11%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+].O>S(=O)(=O)(O)O>[CH2:10]([C:3]1[C:4]([F:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:11]
Reactant: CCc1c(F)ccc(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCc1c(F)c(F)cc([N+](=O)[O-])c1F
Yield: 81.6 %

Procedure:
2,3,6-Trifluoro-1-ethylbenzene (1.09 g) is dissolved in conc. sulfuric acid (5.5 ml), and thereto is added with stirring a mixture of potassium nitrate (0.83 g) in conc. sulfuric acid (4 ml) at room temperature, and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into cold water (100 ml) and is extracted with diethyl ether. The ether layer is washed with aqueous sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.14 g), as yellow oil.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=1.[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.CC(=O)OCC>CCCCCC>[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2[C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=2)[CH2:16][CH2:17]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)c2c(c1=O)NC(=O)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2OCC(=O)N3)c1

Procedure:
The title compound of step 2 was reacted with 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to Example 224, step 5. Silica gel chromatography (40-100% EA in hexane over 8 min) gave the title compound. 1H NMR: (DMSO-d6, 400 MHz) δ ppm 0.27-0.33 (m, 2H) 0.51-0.57 (m, 2H) 1.11 (t, J=7.33 Hz, 3H) 1.14-1.22 (m, 1H, partially obscured) 3.22-3.28 (m, 2H) 3.51 (s, 3H) 3.96 (d, J=7.07 Hz, 2H) 4.54 (s, 2H) 7.27 (d, J=8.84 Hz, 1H) 7.52 (s, 1H) 7.67 (d, J=2.02 Hz, 1H) 7.79-7.92 (m, 1H) 10.10 (s, 1H) LCMS: 419 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccncc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 64 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 4-methylpyridine-3-boronic acid (128 mg, 0.94 mmol) were reacted. After purification the title compound (96 mg, 64% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 8.50 (bm, 1H), 8.47 (s, 1H), 7.95 (a d, J=8.3 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.69 (apparent d, J=7.0 Hz, 1H), 2.96 (m, 1H), 2.10(s, 3H), 0.88 (m, 2H), 0.62 (m, 2H). MS APCI, m/z=320, HPLC 1.55 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH:25]=[N:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27])[CH3:30]
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)C=Nc1cccc(Nc2nc(N(CC(=O)OCC)c3cccc(N=CC(=O)OCC)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate were reacted together to give N2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 25.65 min.; purity: 92.5%; MS (m/e): 569.08 (MH+).
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:4][CH2:5][CH2:6][OH:8])[C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([OH:13])=[O:12])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: NCCCO
Product: O=C(O)c1ccc(C(=O)N(CCCO)CCCO)cc1
Yield: 171.6 %

Procedure:
Into a 500 mL separable flask, 48.1 g of dimethyl terephthalate (manufactured by Wako Pure Chemical Industries, Ltd.) and 112 g of 3-amino-1-propanol (manufactured by Wako Pure Chemical Industries, Ltd.) were placed and subjected to heat drying at 135° C. for 6.5 hours under nitrogen gas stream. To the reaction mixture, isopropyl alcohol was slowly added to thereby provide 59.8 g of N,N-bis(3-hydroxypropyl)terephthalic acid amide, which is an amide group-containing diol. Under a nitrogen gas atmosphere, into a reactor equipped with a mixer, 8.72 g of N,N-bis(3-hydroxypropyl)terephthalic acid amide, 29.8 g of polyethylene glycol (trade name: PEG2000U, manufactured by NOF CORPORATION), and 50 g of dehydrated dimethylacetamide (organic solvent, manufactured by Wako Pure Chemical Industries, Ltd.) were placed and heated at 100° C. under stirring to thereby provide a uniform solution. To this solution, a solution prepared by dissolving 11.5 g of 4,4-diphenylmethane diisocyanate (manufactured by Wako Pure Chemical Industries, Ltd.) in 10 g of dehydrated dimethylacetamide was gradually dropped. After the dropping was completed, the solution was heated for an hour under stirring. The reaction solution was cooled to 80° C. and subsequently reprecipitation was caused with 620 g of acetonitrile. The solid precipitate was isolated by filtration and then washed twice with 160 g of acetonitrile. Thus, a polymer was obtained.
Reaction SMILES: [N:1]([P:6]([Cl:8])Cl)([CH2:4][CH3:5])[CH2:2][CH3:3].[CH:9]1([Mg]Cl)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH2:4]([N:1]([P:6]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[Cl:8])[CH2:2][CH3:3])[CH3:5]
Reactant: CCN(CC)P(Cl)Cl
Reactant: Cl[Mg]C1CCCCC1
Product: CCN(CC)P(Cl)C1CCCCC1
Yield: 57.5 %

Procedure:
U.S. Pat. No. 2,934,564 relates to compounds of the general formula R2PX wherein R represents an alkyl or aryl group and X represents chlorine, bromine or iodine. For example, the reaction of Me2NPCl2 (0.42 mole) with p-tolylmagnesium bromide (0.84 mole) produces dimethylamino-di-p-tolylphosphine. The isolated dimethylamino-di-p-tolylphosphine (31.88 mmoles) was treated with 1428 cc (63.75 mmoles) of anhydrous HCl yielding di-p-tolylchlorophosphine, which was purified by distillation. Similarly, Burg, et al. (J.A.C.S. 80, 1107-09, 1958) disclose the preparation of chlorodimethylphosphine from Me2NPCl2 and suggest the viability of a Grignard route to R2PR'-type phosphines. K. Issleib, et al. (Chem. Berichte 29, 2682-3008, 1959) have shown that Et2NPCl2 (Et=ethyl) and cyclohexylmagnesium chloride react in a 1:1.25 molar ratio to form diethylaminocyclohexylchlorophosphine in 57.5% yield. The authors suggest this reaction can be exploited to prepare unsymmetrical chlorophosphines of the type RR'PCl, but no mention is made of the possibility of further reaction to unsymmetrical tertiary phosphines of the type RR'R"P.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:20])=[CH:4][CH:3]=1.[CH:23](O)=[O:24]>C1(C)C=CC=CC=1>[CH:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:20])=[CH:21][CH:22]=1)=[O:24]
Reactant: COc1ccc2c(c1)CCN(CCc1ccc(N)cc1)C2C
Reactant: O=CO
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(CCc1ccc(NC=O)cc1)C2C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (16.8 g, 0.057 m) in 800 ml toluene was added formic acid (25.0 g, 0.5 m). The reaction was brought to reflux, and water was collected by a Dean-Stark apparatus. After 1 hour, the reaction was poured into ice water (500 g) and basified to pH 11-12 with 10% NaOH. The toluene layer was separated, and the aqueous layer was extracted further with toluene (1×200 ml) and then with chloroform (2×200 ml). The organic extracts were combined, dried and concentrated to an oil. The oil was dissolved in 100 ml ether and a solid formed which was filtered off and dried to give N-(4-formamidophenethyl)-1,2,3,4-tetrahydro-6 -methoxy-1-methylisoquinoline, wt. 12.0 g (71%), m.p. 93°-96°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:16]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[O:38][CH3:39])=[C:17]([O:27][CH2:28][CH2:29][OH:30])[N:18]=[C:19]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)[N:20]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[OH-].[Na+:41]>O>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N-:14][C:15]2[C:16]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[O:38][CH3:39])=[C:17]([O:27][CH2:28][CH2:29][OH:30])[N:18]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:1])[CH3:3].[Na+:41]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Oc1c([N-]S(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A mixture of bosentan (2 g) in de-ionized water (24 mL) was heated to 50° C. followed by the addition of sodium hydroxide (0.175 g). The reaction mixture was stirred for 3.5 hours at the same temperature and the solid was filtered, washed with de-ionized water (6 mL) and dried under hot air oven at 55° C. to 60° C. to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1CCl>C1COCC1>[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1[N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: Cc1cc(C)c(CCl)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C)C)c(C)c1
Temperature: 25 °C

Procedure:
To a mixture of THF (20 mL) and dimethylamine (20 mL, 40% wt in water) at 0° C. was added 2,4,6-trimethylbenzyl chloride (5 g, 29.64 mmol). The mixture was allowed to warm up to room temperature and stirred for 4 h before THF was evaporated and the aqueous residue was extracted with ether. The organic layer was worked up and concentrated as usual to give 2,4,6-trimethylphenyl-dimethylamine in quantitative yleld. This compound was then nitrated and the resulted nitro compound reduced to the corresponding aniline as demonstrated in Example 14.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:19][C:9]2[N:7]3[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]3=[N:11][C:10]=2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:23]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(Cl)cc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. 1H-NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (d, J=9.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.18 (dd, J=1.8, 9.5 Hz, 1H), 6.55 (s, 1H), 5.59 (broad, 1H), 4.99 (d, J=5.6 Hz, 2H), 2.34 (s, 3H); m/e+ 419 for C19H14Cl3N5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N+:16]([O-])=O)[CH:7]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([NH2:16])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])cc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-nitronaphthalen-1-yl)-acetic acid ethyl ester (3 g, 11.58 mmol) and 10% Pd/C (300 mg) in EtOH (100 mL) was stirred under H2 atmosphere (45 psi) at RT overnight. The mixture was filtered over Celite® and washed with EtOH. The filtrate was concentrated to afford (3-aminonaphthalen-1-yl)-acetic acid ethyl ester, which was put to the next reaction without further purification. 1H NMR (300 MHz, DMSO-d6), δ 7.65 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 7.08 (t, J=8.1 Hz, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 5.35 (s, 2H), 4.06 (d, J=7.2 Hz, 2H), 3.94 (s, 2H), 1.14 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 260 (M+H+).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22].C(N(CC)CC)C>C(Cl)Cl>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oleyl alcohol (26.8 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled oleyl alcohol with vigorous stirring in about 2 hours. Triethylamine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCl) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield oleyl methacrylate in good yields. Oleyl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([O:15]C)=O)=[N:10][N:9]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:15])=[N:10][N:9]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1nnc(-c2cnc(Cl)cc2NC(C)C)o1
Solvent: CO
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(C(=O)N2CCOCC2)o1

Procedure:
A solution of methyl 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (66) (150 mg, 0.51 mmol) in morpholine (1 mL) and MeOH (1 mL) was heated at 80° C. for 2 h. The reaction mass was concentrated under reduced pressure. The crude material obtained was triturated with diethyl ether and filtered to get the desired compound, (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanone. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.88 min; LCMS (ES-API), m/z 352.7 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.S(Cl)([Cl:15])=O>>[CH3:1][N:2]=[C:3]([Cl:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1ccc(OC)cc1
Product: CN=C(Cl)c1ccc(OC)cc1
Yield: 76.7 %

Procedure:
N-Methyl 4-methoxybenzamide (13.95 g, 84.5 mmole) was placed in a 50 ml round bottom flask equipped with magnetic stirrer, heating mantle, condenser and base trap. Thionyl chloride (33 g, 278 mmole) was added. The reaction was stirred and heated at reflux until gas evolution ceased (three hours). The excess thionyl chloride was distilled at ca. 15 mm Hg, and the product distilled at 75°-80° C. (0.1 mm Hg) to yield 11.9 g (76%) of the title compound as a clear colorless liquid.
Reaction SMILES: C[NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13](=[O:15])[CH3:14])[CH:7]=1)(=[O:5])=[O:4].CN>>[C:13]([C:8]1[CH:7]=[C:6]([S:3]([NH2:2])(=[O:4])=[O:5])[CH:11]=[CH:10][C:9]=1[OH:12])(=[O:15])[CH3:14]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(C)=O)c1
Agent: CN
Product: CC(=O)c1cc(S(N)(=O)=O)ccc1O

Procedure:
The title compound was prepared in a similar manner as for the preparation of N-methyl-3-acetyl-4-hydroxy-benzenesulfonic acid amide, but substituting ammonia for mono methyl amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:10][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:8][CH3:9])=[N:5][CH:6]=1
Reactant: COc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
5.76 g (40.1 mmol) of 4-chloro-2-methoxypyridine was dissolved in 20 ml of dimethylformamide, and a dimethylformamide (20 ml) solution of 8.01 g of N-bromosuccinimide (98%, 44.1 mmol) was dropwise added over a period of 30 minutes. After stirring at room temperature for 2 days, an unreacted material was confirmed, and thus 2.85 g of N-bromosuccinimide (98%, 16 mmol) was further added, followed by stirring at room temperature further for 3 days. The reaction mixture was poured into 250 ml of water, followed by extraction with ethyl ether (100 ml each) three times. The organic layer was washed with water (100 ml), a sodium thiosulfate aqueous solution (100 ml) and then a saturated sodium chloride solution (100 ml), dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 7.10 g (yield: 30%) of 5-bromo-4-chloro-2-methoxypyridine.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].O>CC(C)=O>[C:1]([CH2:3][CH:4]([OH:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16])#[N:2]
Reactant: N#CCC(O)Cc1cccc(C(O)c2ccccc2)c1
Solvent: CC(C)=O
Solvent: O
Product: N#CCC(O)Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.08 h

Procedure:
7.35 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydride per 100 ml was added with stirring at 0° C to 7.8 g of 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in 78 ml of acetone and the mixture was allowed to stand at 0° C for 5 minutes and was then poured into water with stirring. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 7.4 g of 3-(3'-cyano-2'-hydroxypropyl)-benzophenone which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]([NH2:18])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH:5]=[N:6][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:18][C:15]2[N:16]=[CH:17][C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:21][CH:22]=1
Reactant: Nc1ncc(-c2cncc(F)c2)c2cccnc12
Reactant: Fc1ccc(Br)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1ccc(Nc2ncc(-c3cncc(F)c3)c3cccnc23)nc1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-(5-Fluoro-pyridin-3-yl)-[1,7]naphthyridin-8-ylamine (0.1 g, 0.42 mmol) and 2-bromo-5-fluoropyridine (0.13 g, 0.76 mmol) (Example C) were dissolved in 3 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.084 mmol), cesium carbonate (0.22 g, 0.67 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (43 mg, 0.042 mmol) were added and the reaction mixture was stirred for 20 hrs at 130° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 95:5->30:70 gradient). The desired product was obtained as a light red solid (35 mg, 25%), MS: m/e=336.3 (M+H+).