Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>CN1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)=[CH:6][N:7]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: Brc1ccc(Cc2c[nH]c3ncccc23)cn1
Agent: CN1CCCC1
Product: C[C@H](Nc1ccc(Cc2c[nH]c3ncccc23)cn1)c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 1.67 h
Yield: 27.6 %

Procedure:
A mixture of 3-(6-bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (91, 100 mg, 0.0003 mol) and (S)-1-(4-chloro-phenyl)-ethylamine (92, 0.5 g, 0.003 mol) in N-methylpyrrolidine (3 mL) was stirred at 150° C. in microwave for 100 minutes. The reaction mixture was concentrated under vacuum and the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (P-0075, 0.03 g, 20%). MS (ESI) [M+H+]+=363.18.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[CH3:15].Cl.[O:17]([NH2:19])[CH3:18].N1C=CC=CC=1>C(O)C>[CH3:18][O:17][N:19]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:15])=[C:2]([Br:1])[CH:11]=2)[C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8]1
Reactant: CON
Reactant: Cc1cc2c(cc1Br)C(=O)CCC2(C)C
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCC(C)(C)c2cc(C)c(Br)cc21
Yield: 99.9 %

Procedure:
A solution of 7-bromo-1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene (1.02 g, 3.82 mmol), methoxylamine hydrochloride (0.638 mg, 7.63 mmol) and pyridine (0.93 mL, 11.46 mmol) in ethanol (30 mL) was refluxed for 3 hours. The mixture was concentrated in vacuo then diluted with water and extracted twice with ethyl acetate. The combined organic layer was dried (Mg2SO4), filtered and evaporated to give 1.13 g of 7-bromo-1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene-O-methyloxime as a yellow oil (quantitative) and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.25 (s, 6 H), 1.75 (t, J=6.9 Hz, 2 H), 2.38 (s, 3 H), 2.73 (t, J=6.9 Hz, 2 H), 3.98 (s, 3 H), 7.17 (s, 1 H), 8.11 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH3:17])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1O

Procedure:
5-Methylsalicylic acid was reacted with methanol and sulphuric acid by the general method of Brunner (Monatsh. 1913, 34, 916) to give methyl 5-methylsalicylate, b.p. 115°-116° C./10 mmHg. This ester (12.0 g) was heated together with benzyl chloride (9.1 g) and anhydrous potassium carbonate (5.0 g) in dry sulpholane (90 ml) at 100° C. for 22 hours. The mixture was then poured into a mixture of ice and water (1200 ml) to give crude methyl 2-benzyloxy-5-methylbenzoate (17.6 g). This ester (4.3 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 100 ml) for 2 hours and the mixture was then cooled, diluted with water, and acidified to pH 2 by treatment with concentrated hydrochloric acid to give 2-benzyloxy-5-methylbenzoic acid (3.65 g), m.p. 98°-100° C.
Reaction SMILES: B(O)O.Br[C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[O:9]1[C:8]([CH:10]=[O:11])=[CH:7][CH:6]=[C:5]1[C:13]1[O:12][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1ccc(-c2ccco2)o1

Procedure:
[2,2′-bifuran]-5-carbaldehyde was prepared using the general boronic acid coupling procedure with 5-bromofuran-2-carbaldehyde and furan-2-ylboronic acid (24 mg, 93 mg theoretical, 25.8%). LC-MS m/z 163 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(Cl)cc2C#N)cn1
Yield: 63 %

Procedure:
As described for example 84a, 5-chloro-2-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. After aqueous workup and crystallization from ethyl acetate the title compound was obtained as a white solid (yield: 63%). MS: m/e=218.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH3:32]>CO>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1c(C#CCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Solvent: CO
Product: CCCc1c(CCCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 86 %

Procedure:
Catalytic hydrogenation of 2-[6-(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)-5-hexynyloxy]benzenepropanoic acid methyl ester in methanol was carried out using the procedure of example 51. 2-[6-(3,4-Dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)hexyloxy]benzenepropanoic acid methyl ester was obtained as a colorless oil, in 86% yield.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:3])=[CH:10][CH:11]=1
Reactant: CI
Reactant: OCCCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 88 %

Procedure:
Sodium hydride (purity: 55%, 434 mg) and methyl iodide (0.62 mL) were added to a solution of 4-(4-bromophenyl)butan-1-ol obtained in Reference Example 5-21(1) in N,N-dimethylformamide (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→20:1→10:1) to give the title compound (1.06 g, 88%).
Reaction SMILES: [N+:1]([C:4]([C:16](=[O:18])[CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH2:21][CH2:20]1>C(O)C>[CH3:17][C:16]1[O:18][C:25]2([N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[CH:30]([CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:12]([F:13])([F:14])[F:15])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:29][CH2:28][CH2:27][CH2:26]2
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC(=O)C(=Cc1ccccc1C(F)(F)F)[N+](=O)[O-]
Solvent: CCO
Product: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2CCCCC2(N2CCOCC2)O1

Procedure:
10.4 g (40 mmol) of 2-nitro-1-(2-trifluoromethylphenyl)-but-1-en-3-one and 6.7 g (40 mmol) of 1-morpholinocyclohexene are brought together in 20 ml of ethanol at room temperature. An exothermic reaction takes place and after a short time the product crystallizes in pale yellow crystals as an isomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:13]2[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:30])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(Nc2ncccc2NS(=O)(=O)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncccc2N(C)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.3 mmol) of the compound of Example 4 was dissolved in 5 ml of dimethylformamide. 60 mg (1.5 mmol) of sodium hydride (60%) was added to the solution. The resulting solution was stirred at room temperature for 30 min and 95 μl (1.5 mmol) of methyl iodide was added thereto.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)O[C:5](=O)[C:4]=1[C:17]([O:19][CH3:20])=[O:18].[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:28]=3)[C:5]=2[C:4]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccc(C)cc2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(C)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-p-tolyl-2H-pyran-3-carboxylate (290 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 7 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 334 mg (74%) of methyl 8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:39]([C:40]([F:41])([F:43])[F:42])[C:32]=2[F:31])[CH:6]=1
Reactant: Fc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2F)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.7 g, 0.002 mol) in DMF (10 mL), was added 2-fluoro-3-(trifluoromethyl)benzyl bromide (0.5 g, 0.002 mol) and powdered potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.84 g in 72% yield. 1H NMR (CDCl3) δ 7.35 (t, 1H), 7.17 (m, 12H), 6.85 (t, 2H), 6.63 (s, 1H), 6.59 (t, 1H), 4.16 (t, 1H), 3.69 (s, 3H), 3.68 (s, 2H), 3.63 (t, 2H), 3.57 (d, 2H), 3.10 (d, 2H), 2.67 (t, 2H), 1.82 (t, 2H). 13C NMR (CDCl3) δ 173.4, 160.4, 144.8, 136.6, 130.8, 130.8, 129.7, 129.6, 129.4, 127.7, 126.8, 124.9, 123.1, 122.8, 116.8, 114.5, 66.3, 61.4, 53.5, 52.4, 51.8, 51.1, 42.7, 28.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C2C=[CH:15][C:16]3[CH2:17][C@H:18]4[N:29]([CH:30]=O)[CH2:28][CH2:27][C@@:24]5([C:25]=3[CH:26]=2)[C@H:19]4[CH2:20][CH2:21][CH2:22][CH2:23]5)C=CC=CC=1.[C:32]([O:35][CH2:36][CH3:37])(=O)[CH3:33].O>O1CCCC1>[O:35]([C:36]1[CH:37]=[CH:15][C:16]2[CH2:17][C@H:18]3[N:29]([CH3:30])[CH2:28][CH2:27][C@@:24]4([C:25]=2[CH:26]=1)[C@H:19]3[CH2:20][CH2:21][CH2:22][CH2:23]4)[C:32]1[CH:24]=[CH:25][CH:16]=[CH:15][CH:33]=1
Reactant: CCOC(C)=O
Reactant: O=CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(-c2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 73 %

Procedure:
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenyl-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hq) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH:9]([CH2:12][O:13][CH3:14])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([CH2:19][CH2:20][C:21](Cl)=[O:22])([O:17][CH3:18])=[O:16].[OH-].[Na+]>C1C=CC=CC=1>[C:1]1([C:7]2([C:21](=[O:22])[CH2:20][CH2:19][C:15]([O:17][CH3:18])=[O:16])[NH:11][CH2:10][CH:9]([CH2:12][O:13][CH3:14])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCC1CNC(c2ccccc2)O1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COCC1CNC(C(=O)CCC(=O)OC)(c2ccccc2)O1

Procedure:
To 19.3 milliliters of 25 percent w/v, 2-phenyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene with 3.8 grams of 3-carbomethoxyproprionyl chloride was added 2.0 grams of 50% sodium hydroxide. After the reaction was complete the mixture was washed with water, separated, dried and the organic solvent removed in vacuo. There was obtained 6.8 grams of the title compound, nD30 1.4913. Analytical data supports the structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].Br[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>CN(C)C=O>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1

Procedure:
A mixture of 6.3 g. of sodium imidazole, 100 ml. of dimethylformamide and 19.7 g. of N-(4-bromobutyl)-phthalimide was heated on a steam bath for 6 hours and then concentrated to remove volatile material. The residue was boiled with 150 ml. of toluene and the toluene layer was decanted and concentrated. The residue was triturated with diethyl ether and cooled, giving N-[4-(1H-imidazol-1-yl)butyl]-isoindole-1,3(2H)-dione (m.p. 75°-77° C.) which was recovered by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([O:15]C)=O)[CH:4]=1.O.[NH2:18][NH2:19]>CC(O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([NH:18][NH2:19])=[O:15])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2ccccc2n1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NN)nc2ccccc12
Temperature: 80 °C

Procedure:
The methyl 4-methoxyquinoline-2-carboxylate (1 eq) was dissolved in i-PrOH (0.75 M) and then hydrazine monohydrate (10 eq) was added. The reaction mixture was heated at 80° C. overnight and then the solvent was evaporated under reduced pressure and the crude product was used in the next step without purification. MS (ES) C11H11N3O2 required: 217, found: 218 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[C:11](Cl)[N:10]=1>>[Cl:8][C:9]1[N:10]=[C:11]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[C:13]([I:15])[CH:14]=1
Reactant: NC1CCCCC1
Reactant: Clc1cc(I)cc(Cl)n1
Product: Clc1cc(I)cc(NC2CCCCC2)n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Cyclohexanamine (4.0 mL, 34.9 mmol) was added to 2,6-dichloro-4-iodo-pyridine (954 mg, 3.48 mmol) in a microwave tube and subjected to 300 watts at 150° C. for 30 minutes in a Biotage Microwave Reactor. The crude product was partitioned with water, dichloromethane and the organics combined and concentrated to dryness. The residue was partially purified using silica gel flash chromatography eluting with 2% ethyl acetate, 98% hexanes to give 916 mg 6-chloro-N-cyclohexyl-4-iodopyridin-2-amine as a purple gum. This material was dissolved in 15 mL DMF and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (666 mg, 1.98 mmol) added followed by addition of potassium acetate (400 mg, 4.07 mmol). The mixture was degassed with nitrogen and 1,1′-bis(diphenylphosphino)-ferrocene)dichloropalladium(II) complex with dichloromethane (222 mg, 0.272 mmol) added and the reaction mixture heated at 75° C. for 4 hours and then cooled to room temperature and partitioned with water, ethyl acetate. The organics were combined, concentrated to dryness and purified by silica gel flash chromatography eluting with a gradient from 3% ethyl acetate, 97% hexanes to 6% ethyl acetate, 94% hexanes to provide the title compound as a clear gum in 73% yield. MS (DCI+) m/z 337.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([NH2:24])[CH:18]=1>N1C=CC=CC=1>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([NH:24][S:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:12][CH3:13])(=[O:10])=[O:9])[CH:18]=1
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 809.2 %

Procedure:
5-Chloro-2-methoxybenzenesulfonyl chloride (5.77 g, 2.39 mmol) was added to a solution of 3-amino-4-hydroxy-benzoic acid methyl ester (example 1, step 1; 4.00 g, 23.9 mmol) in pyridine (38 mL). The homogeneous solution was stirred at room temperature for 72 h, then partitioned between ethyl acetate and 2 M aq. hydrochloric acid solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. The residue was triturated in ethyl acetate to furnish 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (7.19 g, 81%). Pink solid, MS (ISP)=370.0 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2nc1C
Product: CCOc1cc2c(Nc3ccc(OC)cc3)c(C#N)cnc2nc1C

Procedure:
A mixture of 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carbonitrile (2.66 g), 4-methoxyaniline (1.35 g) and IMS (50 ml) was boiled under reflux for 2.5 hours. The mixture was cooled in ice and the precipitate was collected by filtration. This solid was boiled in IMS (50 ml), with 5M sodium hydroxide solution (1.2 ml) under reflux for 30 minutes. The mixture was cooled and evaporated. The residue was purified by flash chromatography on silica using dichloromethane/IMS, 19:1 as the mobile phase to give a solid which was ground up in IMS (15 ml) and filtered to give 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carbonitrile, m.p. 190°-192° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.[C:9]([C:15](OC)=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[OH:16][C:15]1[N:3]2[N:4]=[C:5]([CH2:7][OH:8])[N:6]=[C:2]2[N:1]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=1
Reactant: Nc1n[nH]c(CO)n1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(O)n2nc(CO)nc2n1
Temperature: 30 °C
Reaction time: 20 h

Procedure:
In 1.7 liters of methanol was suspended 60 g of 3-amino -5-hydroxymethyl-1,2,4-triazole and 75 ml of dimethyl acetylenedicarboxylate was added to the suspension, and the mixture was stirred at 30 ° C for 20 hours. Precipitates were collected by filtration, washed with methanol and then dried to obtain 25.7 g of the title compound.
Reaction SMILES: [CH:1]12[CH2:9][CH:4]([CH2:5][C:6]1=NO)[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]2=1.[Na].[OH2:15]>C(O)C.C(Cl)(Cl)Cl>[CH:1]12[CH2:9][CH:4]([CH2:5][C:6]1=[O:15])[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]2=1
Reactant: O
Reactant: ON=C1CC2CC1c1ccccc12
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1CC2CC1c1ccccc12
Temperature: 25 °C

Procedure:
A solution of benzonorbornen-2-one oxime (2g.) in absolute ethanol (120ml.) was heated to reflux under nitrogen and sodium metal (12 g.) was added in small portions with continuous stirring. The reaction mixture was then refluxed for 30 minutes. This viscous suspension was then cooled to room temperature, 100 ml. of water added and the reaction mixture agitated until a clear solution was obtained. This was extracted with ether and the ether extract worked up to give an oil which was dissolved in chloroform and extracted with 10% HCl solution. Removal of water and excess HCl under vacuum from this extract gave a white solid (1g., 40%). The white solid was analyzed by infra-red, nuclear magnetic resonance and elemental analysis techniques and was determined to be the 1,2,3,4-tetrahydro-1,4-methanonaphthalen-endo-2-amine hydrochloride, C11H14NCl (m.p. 230°-231°C). Basification of a sample of this material with 10% NaOH gave, on ether extraction, the required amine as a pale yellow oil which was also analyzed by infra-red, and nuclear magnetic resonance techniques, and the empirical formula was determined to be C11H13N.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12]([O-:15])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([O:15][CH3:12])=[CH:9][CH:2]=2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)c(C=O)c(Cl)c2)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a mixture of 2,6-dichloro-4-hydroxybenzaldehyde (1.00 g, 5.24 mmol) and K2CO3 (1.45 g, 10.5 mmol) in THF (25 mL) under N2 was added dropwise1-bromomethyl-4-methoxybenzene (1.10 mL, 7.85 mmol). The reaction was heated at 65° C. for 3 h, at 45° C. overnight then at 65° C. for 3 hr. The reaction was allowed to cool to ambient temperature then was filtered and the filtrate concentrated under reduced pressure. The concentrate was diluted with EtOAc (150 mL) and extracted with water (30 mL). The organic phase was dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography using a gradient of 5-15% EtOAc/heptane as eluent to afford 2,6-dichloro-4-(4-methoxybenzyloxy)-benzaldehyde as a white solid. MS (m/z) 311.0 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 10.28 (s, 1H), 7.40 (d, J=8.59 Hz, 2H), 7.29 (s, 2H), 6.97 (d, J=8.72 Hz, 2H), 5.19 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C@H:10]([NH2:12])[CH3:11])[CH:6]=[N:5]1.C(C1C=NN(C[C:23]([O:25][CH3:26])=[O:24])C=1C)(=O)C>>[ClH:1].[ClH:1].[NH2:12][CH:10]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:23]([O:25][CH3:26])=[O:24])[C:8]=1[CH3:9])[CH3:11]
Reactant: COC(=O)Cn1ncc(C(C)=O)c1C
Reactant: Cc1c([C@@H](C)N)cnn1C
Agent: Cl
Product: COC(=O)Cn1ncc(C(C)N)c1C
Yield: 6.6 %

Procedure:
The title compound was prepared in 6.6% yield by the process as described for (R)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanamine dihydrochloride (Amine 2) using methyl 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetate (Step A8A) as a starting material. 1H NMR (300 MHz, DMSO-d5) δ 1.48 (3H, d, J=6.0 Hz), 2.22 (3H, s), 3.69 (3H, s), 4.29-4.33 (1H, m), 5.05 (2H, s), 7.59 (1H, s), 8.26 (3H, brs).