Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11](O)[CH2:12][OH:13]>>[C:1]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: OCCO
Product: CCCCCCCC(=O)OCCO

Procedure:
Anhydride of caprylic acid (0.477 mol; 129 g) was dropwise added into boiling dry ethylene glycol (3.16 mol; 196 g) and the mixture was refluxed for further 4 hours. The mixture was cooled, extracted twice with benzene (100+20 ml), benzene was evaporated in a rotation evaporator, and the residue was distilled. 2-Hydroxyethyl caprylate was obtained in the yield of 142.75 g (159% of theory), which is the evidence that almost 2/3 of caprylic acid formed was esterified with glycol under the experimental conditions. The raw fractions had purity 88.9 to 97.5% of 2-hydroxyethyl caprylate. Further procedure was carried out according to example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([F:22])[CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1F
Temperature: 40 °C
Yield: 99.5 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.2 g, 0.71 mmol) in pyridine (2 mL), 0.071 mL (0.78 mmol) of 3-fluoro-4-methylbenzoyl chloride were added. The mixture was heated at 40° C. for 4 h and the solvent was evaporated. The crude mixture was extracted between ethyl acetate and water, the organic layer was dried (MgSO4) and evaporated to give the title compound (0.295 g, 88% of yield) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(CN)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cc(CNS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 48.7 mg of 5-[6-(aminomethyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide and 26.1 mg triethylamine in 1 ml anhydrous dichloromethane is stirred at room temperature. Under nitrogen atmosphere, 14 mg methanesulfonyl chloride is added. The reaction mixture is stirred at room temperature for 14 h. The solvent is removed under pressure and the residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
4-(3-Hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 61.6 mmol), 3-trifluoromethylphenol (19.4 g, 64.7 mmol), triphenylphosphine (1.40 g, 73.9 mmol) and tetrahydrofuran (200 ml) were mixed. While stirring the mixture at room temperature, DEAD (21.1 ml, 80.0 mmol) was added thereto dropwise and heated at reflux for 2 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=87:13) to afford the title compound as a pale yellow oil (20.5 g, yield 86%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Si:11]([O:10][CH2:9][C:6]1[S:5][S:4][C:3]([CH2:2][O:1][C:20]2[CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:19]=2[Cl:18])=[CH:8][CH:7]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2cc(C(F)(F)F)ccc2Cl)SS1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) (200 mg, 0.688 mmol) in 5 mL dry THF was added a solution of 2-chloro-5-(trifluoromethyl) phenol (271 mg, 180 μL, 1.38 mmol) in 5 mL of THF, followed by the addition of triphenylphosphine (220 mg, 0.83 mmol). The resulting solution was cooled to 0° C., then 140 μL (155 mg, 0.89 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. for 30 min and then the ice-water bath was removed. The reaction mixture was stirred at rt for 17 h. For isolation of the products the reaction mixture was chromatographed directly on a silica gel column, using ethyl acetate-hexane (1:3) as eluant, to yield 3-[(tert-butyldimethylsilyloxy)methyl]-6-[(2-chloro-5-trifluoromethyl-phenyloxy)methyl]-1,2-dithiin, 200 mg (62%); 1H NMR(CDCl3):δ7.54 (d, J=8, 1 H), 7.23 (d, J=8.4, 1 H), 7.16 (s, 1 H), 6.54 (d, J=6.4, 1 H), 6.42(d, J=6.4, 1 H), 4.78(s, 2 H), 4.31 (s, 2 H), 0.9 (s, 9 H), 0.1 (s, 6 H); MS (EI):m/z 468.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:7]=12.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:7]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwise addition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution was stirred at room temperature for 3 hours, at which time an additional 2.4 mL of 1N sodium hydroxide was added. The solution was stirred at room temperature for overnight and the resulting mixture was diluted with 75 mL of water and acidified using 1N HCl. The insoluble material was separated by filtration and the filter cake was suspended in ethyl acetate and stirred for several minutes before filtering. The filter cake was washed several times with ethyl acetate and dried under high vacuum to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as an off white solid. Yield: 1.6 g (90%); MS [M+H]+ 456.1; 1HNMR (DMSO-d6) δ: 13.9 (bs, 1H), 9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 2.1 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[CH:19][CH:20]=[N:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]2[N:17]4[N:18]=[CH:19][CH:20]=[N:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:25]=[N:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2ccc(Cc3nnc4nccnn34)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5nccnn45)cc3c2)cn1
Temperature: 135 °C

Procedure:
A mixture of 3-bromo-6-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl-quinoline (69 mg, 0.204 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (51 mg, 0.25 mmol), potassium carbonate (56 mg. 0.41 mml), 1,4-dioxane (2 mL) and water (1 mL) was bubbled nitrogen gas through for 10 minutes. After such time dichlorobis(triphenylphosphine)palladium (8 mg, 5 mol %) was added, the vial sealed and heated in a microwave for 1500 seconds at 135° C. The mixture was diluted with dichloromethane and brine, before the organic phase was concentrated onto silica gel and via flash column chromatography (SiO2 4 g, dichloromethane/CH3OH 0-10%) to return the title compound a white solid (11 mg, 16%). Analytical data presented in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](OCC)=[O:12])=[C:7]2[C:16]([O:18]CC)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[C:10]2[NH:9][C:8]3[C:11](=[O:12])[N:22]=[N:23][C:16](=[O:18])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2c(Cl)cccc2c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2c1[nH]c1c(Cl)cccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
To a stirred solution of diethyl 7-chloroindole-2,3-dicarboxylate (0.6 g, 2.0 mM) in ethanol (4 mL) was added hydrazine hydrate (2 mL, 40 mM). The resulting solution was heated to reflux for 3 hrs during which time a white precipitate formed. The solid was filtered, suspended in acetic acid (2 mL), and warmed to reflux for several minutes. The mixture was then cooled to room temperature and the solid filtered and dried. This provided the titled compound as a white solid (0.11 g, 23%), mp >250° C. NMR (d6 -DMSO): 12.92 (s, 1H), 11.66 (s, 2H), 8.08 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz), 7.32 (t, J=8 Hz). MS(CI): 236(M+1).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([F:30])=[C:27]([F:29])[CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)c(F)cc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.575 ml, 4.85 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 151 (1.6 g, 4.85 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.78 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1>C(O)C.N1CCCCC1>[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:8]2[O:7][C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2=[O:16])=[CH:18]1
Reactant: CCOC(=O)C1=C(NCCOC)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(NCCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.2 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.32 g, 2.2 mmol) in ethanol (3.0 mL), piperidine (5 drops) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:13][C:14](=[CH2:16])[CH3:15].C([O-])(O)=O.[Na+]>O>[C:14]([O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])([CH3:16])([CH3:15])[CH3:13]
Reactant: C=C(C)C
Reactant: O=C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H).
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([C:12]#[N:13])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.CC(C)=O>[C:12]([C:9](=[N:6]/[C:3](=[C:2](\[NH2:1])/[C:7]#[N:8])/[C:4]#[N:5])[CH3:10])#[N:13]
Reactant: CC(=O)C#N
Reactant: N#C/C(N)=C(/N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C#N)=N/C(C#N)=C(\N)C#N
Yield: 41 %

Procedure:
10.8 g of diaminomaleonitrile and 10.0 g of acetyl cyanide were added successively to a solution of 1.9 g of p-toluenesulfonic acid in 100 ml of dry diethyl ether. The resulting yellow powder was collected by filtration and dried. The crude product thus obtained was dissolved in 600 ml of acetone and any insoluble insoluble solids were removed by filtration. 900 ml of water was added to the filtrate to obtain α-cyanoethylidenediaminomaleonitrile in 41% yield.
Reaction SMILES: O=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6].N.[BH3-]C#[N:26].[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[NH2:26][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: [BH3-]C#N
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(=O)c2ccccc2)C1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Reaction time: 1.33 h
Yield: 93.4 %

Procedure:
A 25 mL microwave reaction vessel equipped with a stir bar was charged with 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-oxo-2-phenyl-ethyl)-amide (80 mg) and ammonia (1.5 mL, 7 M in methanol). A drop of acetic acid and NaCNBH3 (20 mg) were added to the reaction mixture and subjected to microwave at 80° C. for 80 min. The residue was taken up in ethyl acetate (30 mL) and saturated NaHCO3 (aq.) (30 mL). The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with sat NaHCO3 (3×10 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a solid (75 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48]1([N:54]=[C:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:55]([NH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:56])[CH2:41]1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 50% yield. LCMS for C32H33ClN7O2 (M+H)+: m/z=582.0.
Reaction SMILES: O[C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[O:13])[CH:5]=[CH:4][C:3]1=2.C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[O:13])[CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(c1)CCC[C@@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCCc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S)-5-Hydroxy-5,6,7,8-tetrahydronapthalene-2-carbaldehyde (19.73 mmol) was dissolved in 50 mL of toluene and cooled to 0° C. Diphenylphosphoryl azide (29.6 mmol, 1.5 eq) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (23.07 mmol, 1.2 eq). After stirring at room temperature overnight, the solvent was evaporated. The residue was purified by SiO2 chromatography (5→30% ethyl acetate in dichloromethane) to afford the title compound. MS (m/z): 204.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][C:13]4([CH2:18][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1)[O:17][CH2:16][CH2:15][O:14]4.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.Cl>C(O)C>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][C:13]5([CH2:18][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[O:17][CH2:16][CH2:15][O:14]5)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Agent: Cl
Solvent: CCO
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCC2(C4)OCCO2)ccc1OCc1ccccn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To ethanol (60 mL) were sequentially added 4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane] (5.70 g, 20.2 mmol), 3-Chloro-4-(pyridin-2-ylmethoxyl)-phenylamine (4.78 g, 20.37 mmol), and HCl in ethanol (1N, 4 mL). The suspension was stirred with heating to 80° C., upon which time the contents turn brown and homogeneous. After 12 h, the dark orange-yellow heterogeneous mixture was removed from heating, and allowed to cool to rt. The contents were concentrated down to about 30 mL in volume and the precipitate was collected by filtration as a light-brown solid (10.1 g, 92%). 1H-NMR (DMSO-d6) δ 8.71 (d, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.10 (td, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 7.56 (m, 2H), 7.25 (d, 1H), 5.48 (br, 1H), 5.38 (s, 2H), 3.99 (s, 4H), 3.28 (t, 2H), 3.03 (s, 2H), 1.97 (t, 2H); LCMS RT=2.73 min; [M+H]+=481.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:11]([OH:13])=O.[C:18]([O:22][C:23]([N:25]1[CH2:35][CH2:34][C:28]2[N:29]=[C:30]([NH2:33])[N:31]=[CH:32][C:27]=2[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:35][CH2:34][C:28]2[N:29]=[C:30]([NH:33][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:17])[CH:16]=[C:8]([Cl:7])[CH:9]=3)[N:31]=[CH:32][C:27]=2[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cc(Cl)cc(Cl)c3)ncc2C1
Reaction time: 1 h
Yield: 56.5 %

Procedure:
Oxalyl chloride 1184 μl (13.8 mmol) and two drops of DMF were added to a solution of 3,5-dichlorobenzoic acid 527 mg (2.76 mmol) in CH2Cl2 and stirring was performed for 1 h at RT under nitrogen as inert gas. After removal of the solvent, the 3,5-dichlorobenzoyl chloride was dissolved in pyridine (30 ml). 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 599 mg (2.39 mmol) was added to this solution at 0° C. and stirring was performed for 2 h at 0° C. and then for 2 h at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 573 mg (1.35 mmol, 57% of theoretical) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.C(N(CC)CC)C.[ClH:27].[Cl:28][CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>>[ClH:28].[ClH:27].[CH:36]12[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]1)[CH2:32][N:31]([CH2:30][CH2:29][N:14]1[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:37]2
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 34 %

Procedure:
Prepared by the method described in Example 9 from 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.2 g, 0.020 moles), triethylamine (4.9 g, 0.048 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (5.4 g, 0.024 moles). Recrystallization from methanol yielded the final product (3.3 g) as the dihydrochloride, mp 229°-234° C.