Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:18]([S:19][CH3:20])=[CH:17][C:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15]1.I[CH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CCCCCC>[CH3:13][N:14]1[C:18]([S:19][CH3:20])=[CH:17][C:16]([CH:21]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:22]([O:24][CH3:25])=[O:23])=[N:15]1
Reactant: ICC1CCOCC1
Reactant: COC(=O)Cc1cc(SC)n(C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To a solution of diisopropylamine (4.0 mL) in tetrahydrofuran (60 mL) was slowly added 1.6M hexane solution (16.1 ml) of n-butyllithium at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 15 min, and a solution of methyl [1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]acetate (4.68 g) in tetrahydrofuran (5 mL) was slowly added thereto. The reaction mixture was stirred at −70° C. for 15 min, and 4-(iodomethyl)tetrahydro-2H-pyran (5.80 g) was added thereto. The mixture was stirred overnight at room temperature. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.57 g, yield 37%) as a pale-yellow oil from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 299 (MH+).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:46][CH3:47])[C:38]2[O:43][CH2:42][O:41][CH2:40][C:39]=2[C:44]=1[F:45])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:45][C:44]1[C:39]2[CH2:40][O:41][CH2:42][O:43][C:38]=2[C:37]([O:46][CH3:47])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)COCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
After adding 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 105 mg of {2-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (74 mg) as a light brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH:13]3[O:17][N:16]=[C:15]([C:18]4[CH:27]=[CH:26][C:21]5[NH:22][C:23](=[O:25])[O:24][C:20]=5[CH:19]=4)[CH2:14]3)[CH2:10][CH2:11]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)C1(Cc2ccc(F)cc2)CCN(CC2CC(c3ccc4[nH]c(=O)oc4c3)=NO2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(Cc2ccc(F)cc2)CCN(CC2CC(c3ccc4[nH]c(=O)oc4c3)=NO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
A mixture of 4-(4-fluorobenzyl)-1-[3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazol-5-ylmethyl]piperidine-4-carboxylic acid ethyl ester (390 mg, 0.81 mmol) and 20% aq. NaOH (4.5 mL) in EtOH (4.5 mL) was heated to reflux for 16 hours. After stirring at ambient temperature overnight, the reaction solvent was removed under reduced pressure. The reaction mixture was diluted with water, brought to pH 3 with 1N HCl, and extracted with EtOAc (2×). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (silica, 79:20:1 CH2Cl2/MeOH/AcOH) followed by recrystallization from MeOH/Et2O gave 4-(4-fluorobenzyl)-1-[3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazol-5-ylmethyl]piperidine-4-carboxylic acid (28 mg, 8%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-methoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-2′-methoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg; 7%): m/z (ES+) 395 [MH+].
Reaction SMILES: [C:1]([O:14]CC)(=[O:13])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].Cl>CO>[C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC/C=C/C=C/C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC/C=C/C=C/C(=O)O
Temperature: 60 °C

Procedure:
Ethyl (2E,4E)-dodeca-2,4-dienoate (11.84 g) was dissolved in methanol (130 ml) and 2M aqueous sodium hydroxide solution (35 ml) was added. The reaction mixture was heated to 60° C. until full conversion was observed. After cooling down to room temperature the mixture was acidified with diluted aqueous HCl. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, and solvents were evaporated. The crude product was used for the next step without further purification.
Reaction SMILES: C[C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3]CC(O)=O.[O:29]=[CH:30][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[N+]([O-])([O-])=O.[NH4+].P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+].[OH-].[Na+]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2].O>[OH:27][C@@H:13]1[C@@:12]2([CH3:28])[C@@H:11]([CH2:10][CH2:9][C@@H:8]2[CH:2]([CH:30]=[O:29])[CH3:3])[C@H:16]2[C@@H:15]([C@:20]3([CH3:26])[C:19]([CH2:18][CH2:17]2)=[CH:24][C:23](=[O:25])[CH:22]=[CH:21]3)[CH2:14]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 368.2 %

Procedure:
Alcaligenes faecalis D4020-K15 (FERM BP-204) was cultivated in the following manner. A medium (pH 8.4) was prepared by adding tap water to 1.0 g of deoxycholic acid, 0.1 g of glucose, 0.2 g of ammonium nitrate, 0.12 g of potassium dihydrogen phosphate, 0.61 g of dipotassium hydrogen phosphate, 0.02 g of magnesium sulfate heptahydrate, 0.02 g of yeast extract and 0.1 g of sodium hydroxide to a volume of 100 ml. This medium was placed in a 500 ml Sakaguchi flask and steam-sterilized at 120°C. for 15 minutes. Separately and in advance, the above microbe was grown in the same medium as above on a test tube shaker for one day and a 10 ml portion of the seed culture was added to the above-mentioned 500-ml Sakaguchi flask. The flask was shaken at 30° C. for 2 days. The thus-obtained culture broth was centrifuged to separate a mixture of the cells and the precipitate which had formed during the incubation from the culture supernatant. An aqueous 1 N sodium hydroxide solution was added tosaid mixture in an amount sufficient to adjust the pH to 9, and the resultant mixture was extracted with 200 ml of ethyl acetate. On the otherhand, the culture supernatant was adjusted to pH 9 by adding an aqueous 1N sodium hydroxide solution and then extracted with 200 ml of ethyl acetate.Both the extracts were combined and dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off in a rotary evaporator to give 700mg of 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[N:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:14][NH2:15])[N:8]=[N:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(NN)nnc1Cl
Yield: 60.7 %

Procedure:
4-t-Butyl-3,6-dichloropyridazine (Samaritoni, J. G.; Org. Prep. & Proc. Intl., 1988, 20(2), 117-121) (16 g, 78 mmol) and hydrazine monohydrate (24.7 mL, 780 mmol) in ethanol (250 mL) were heated at reflux for 16 hours. The solvent was removed and hydrochloric acid (5M) was added and the resulting mixture was washed with dichloromethane. The aqueous layer was poured onto ice and ammonium hydroxide was added until the mixture was basic. The mixture was extracted with dichoromethane, dried (MgSO4) filtered and evaporated to give a yellow solid (9.5 g, 61%) 1HNMR (360 MHz, CDCl3) δ 1.46 (9H, s, t Bu), 378 (2H, br s, NH2), 6.84 (1H, br s, NH), 7.10 (1H, s, ArH); MS (ES+) m/e 201 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COCCC1(C(=S)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COCCC1(C(=S)N[C@@H](Cc2ccc(N)cc2)C(=O)OC)CCCC1
Reaction time: 0.33 h
Yield: 106.4 %

Procedure:
To a suspension of N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (4.58 g, 11.6 mmol), zinc dust (7.50 g, 116 mmol) and ammonium chloride (9.20 g, 174 mmol) in methanol (200 mL) was added H2O (100 mL) slowly over 5 min. After stirring for 20 min, the reaction mixture was partitioned between ethyl acetate (400 mL) and sat. ammonium chloride solution (150 mL).The separated aqueous layer was back-extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residual oil was dried under high vacuum for 2 h to give crude 4-amino-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (4.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[C:20](O)(=O)C>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
The compound obtained in (1) above 73 gm was dissolved into 600 ml of acetic acid. To the solution were added 20 ml of 40% perchloric acid and 10% palladium-on-carbon to effect catalytic hydrogenation under 5 atm. After the evaporation of acetic acid and the addition of 100 ml of water, the residue was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated and 100 ml of dichloromethane, 74 gm of sodium carbonate, and 30 ml of thionyl chloride were added to the residue. The mixture was heated under reflux for 3 hours and then cooled to 0° C., and 150 ml of methanol was slowly added, followed by stirring for 12 hours at room temperature. After the addition of 300 ml of ethyl acetate, the resulting product was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 66.7 gm of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=1[O:40][CH3:41]>>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:37])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: COc1cc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)ccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-chloro-3-methoxybenzoic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 608.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].CO>CN(C=O)C>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
83.6 g (0.5 mol) of carbazole are dissolved in 250 ml of dry DMF. This solution is added dropwise at 0° C. to a suspension of 12.0 g (0.4 mol) of sodium hydride in 500 ml of DMF. An 80% oil suspension of NaH is used. After stirring for a further 2 hours at 0° C., 38 ml (0.45 mol) of allyl bromide are added dropwise. After the end of the addition, the mixture is warmed to room temperature within one hour, with stirring. To decompose residual NaH, 100 ml of methanol are also added. The solvent mixture is then removed in vacuo in a rotary evaporator and the residue is extracted with 400 ml of petroleum ether (40°-60° C.). Finally, the petroleum ether extract is filtered and evaporated in a rotary evaporator. The remaining brownish oil is distilled in a high vacuum. This gives 65.1 g of a pale yellow, microcrystalline solid. Melting point: 52°-54° C., boiling point: 112° C./13 Pa. Yield 78.5% of theory.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.Cl[C:33](Cl)(Cl)[C:34](=[O:36])C>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][C:34](=[O:36])[CH3:33])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Reactant: CC(=O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 101.3 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.10 g, 0.22 mmol) in CHCl3 (1 mL) at 0° C. under N2 was added trichloroacetone (30 μL, 0.26 mmol). The mixture was allowed to slowly warn to rt for 1.5 hr. The reaction was then heated at 60° C. for 1.5 h. Cool to rt, add additional trichloroacetone (10 μL) and continue heating at 60° C. for 2 hr. The reaction was concentrated and purified by biotage MPLC (90 g column, 80% ethyl acetate/hexanes) to afford 0.11 g (55%) of N-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide as a solid: 1H NMR (CDCl3) δ 0.84-1.01, 1.61-1.81, 2.04, 2.80-2.86, 3.58-3.64, 4.07-4.13, 4.46, 5.56, 6.56, 7.28-7.51; MS (ESI+) for C27H26Cl2N4O m/z 493 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[NH2:15][OH:16]>C(O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11](=[N:15][OH:16])[NH2:12])=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#Cc1ccc(CC2OCCO2)cc1
Solvent: CCO
Product: NC(=NO)c1ccc(CC2OCCO2)cc1
Yield: 73 %

Procedure:
To a solution of 4-((1,3-dioxolan-2-yl)methyl)benzonitrile (1.40 g, 7.41 mmol) in ethanol (10 mL), was added 50% aqueous hydroxylamine (5 mL), and the resultant mixture was heated at 80° C. for 16 hours. The solvent was evaporated at reduced pressure, and the residue partitioned between ethyl acetate and brine. The organic phase was removed, and the aqueous phase was extracted with further ethyl acetate (×2). The combined organic extracts were dried with aqueous magnesium sulfate and evaporated at reduced pressure to afford the title compound (1.21 g, 73%).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(OCC)(=O)C>C(O)(=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1O
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc3ccccc3o2)cc1
Yield: 6.9 %

Procedure:
In an acetic acid solvent in the presence of sodium acetate (NaOAc) (3.0 eq.), a solution including 2-aminophenol (1.0 eq.) and 4-methoxybenzaldehyde (1.0 eq.) was refluxed. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and acetone (25:1) to obtain a solid Compound 124.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ccc(F)cc2F)CCNCC1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
4-(2,4-Difluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.2 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound as a pale yellow solid (0.08 g). LCMS m/z 214.25 [M+H]+. R.T.=1.06 min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=1[O:11]2
Reactant: Cc1ccccc1Oc1cc(Cl)ccc1C(=O)O
Solvent: CO
Product: Cc1cccc2c(=O)c3ccc(Cl)cc3oc12
Yield: 90 %

Procedure:
The above crude acid (IV: R1 =4-Cl, R3 =H) was cyclized with polyphosphate ester as in Example A to give a 90% yield of 6-chloro-4-methylxanthenone (VI: R1 =6-Cl, Z=CH3), mp (MeOH) 145°-146° C. Anal. (C14H9ClO2) C,H,N.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3C=CC(CN4CCOCC4)=C[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[CH3:62][N:63]1[CH:67]=C(C=O)C=[N:64]1>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[N:64][N:63]([CH3:67])[CH:62]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: Cn1cc(C=O)cn1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cn1
Yield: 88 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 1-Methyl-1H-pyrazole-4-carbaldehyde were reacted to produce the title compound (88%). 1H NMR (d-chloroform): 15.26 (br s, 1H) 8.26 (d, J=8 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 6.45 (m, 1H), 6.41 (m, 1H), 5.99 (s, 1H), 5.70 (s, 1H), 5.31 (t, J=8 Hz, 1H), 4.02 (s, 3H), 3.16 (s, 1H), 3.00 (s, 1H), 2.68 (d, J=8 Hz, 1H), 2.29 (d, J=9 Hz, 1H), 1.66 (d, J=10 Hz, 1H). MS: 385.06 (M+H). HPLC retention time: 1.90 minutes (G Method).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(OCCl)c1cccc(F)c1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.35 g of chloromethyl 3-fluorobenzoate was added, and the mixture was stirred at 70° C. for 6 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.12 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3-fluorobenzoate (present compound (37)).