Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=2)[CH2:7]1>N1C=CC=CC=1.C(O)C>[OH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:2][OH:3])[CH3:19])=[CH:14][CH:13]=2)[CH2:7]1
Reactant: NO
Reactant: CC(=O)c1ccc(N2CC(CO)OC2=O)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(N2CC(CO)OC2=O)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Hydroxylamine hydrochloride (5 g) was added to a solution of 5 g 5-hydroxymethyl-3-(4-acetylphenyl)-2-oxazolidinone in 40 ml of 1:1 pyridine/ethanol. The mixture was stirred at reflux under nitrogen for 4 hours. After cooling to room temperature, the mixture was evaporated and the residue was triturated with water and dilute aqueous hydrochloric acid and collected. Recrystallization from aqueous ethanol gave 4.61 g pure 5-hydroxymethyl-3-[4-(1-hydroxyiminoethyl)phenyl]-2-oxazolidinone, m.p. 189.5°-190° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:15]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1-c1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1ccccc1-c1ccccc1
Yield: 70.1 %

Procedure:
Under an atmosphere of argon, 2,2′-dibromobiphenyl (9.5 g, 30 mmole), phenylboronic acid (3.7 g, 30 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (1.0 g, 0.87 mmole, 3% Pd) were dissolved into toluene (75 ml). To the obtained solution, an aqueous solution of sodium carbonate (9.7 g, 92 mmole, 3 eq/46 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a dark yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and a colorless oil (6.5 g, 70%) was obtained.
Reaction SMILES: Cl.[CH:2]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:15][C:16]1[O:17][C:18]([CH3:25])=[C:19]([CH3:24])[C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH:2]1([N:7]([C:21]([C:20]2[C:19]([CH3:24])=[C:18]([CH3:25])[O:17][C:16]=2[CH3:15])=[O:22])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Reactant: ONC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1oc(C)c(C(=O)N(O)C2CCCC2)c1C
Temperature: 25 °C

Procedure:
27.5 Parts of N-cyclopentylhydroxylamine hydrochloride is dissolved in 200 parts of dichloromethane; a solution of 33.6 parts of sodium hydrogen carbonate in 300 parts of water is then added. At room temperature and while stirring thoroughly, 34.5 parts of 2,4,5-trimethylfuran-3-carboxylic chloride is dripped into this mixture. After the mixture has been stirred for 2 hours the dichloromethane phase is separated, dried over anhydrous sodium sulfate and evaporated. There is obtained 36 parts of N-cyclopentyl-2,4,5-trimethylfuran-3-hydroxamic acid in the form of an oil.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[C:26]#[CH:27]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:25](=[O:28])[C:26]#[CH:27])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: C#CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propynoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-propynoyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1.C(=O)=O.C(O)C.Cl.C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[CH:8]=[CH:7][C:6]([CH:28]=[O:29])=[CH:5][C:4]=3[C:3]2([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 9,9-diethyl-2,7-dibromofluorene (59.38 g., 0.1563 mol.), in THF (325 ml), cooled in dry ice-ethanol bath, n-butyl lithium (104 ml of 1.6M solution in hexanes, 0.1664 mol, 1.06 eq.) was added dropwise over 25 minutes. After 20 minutes, DMF (17 ml, 0.22 mol.) in THF (30 ml) was added, and the mixture was stirred in the cooling bath for 1.5 hours, and outside the bath for 1 hour. The reaction was then cooled to 5° C., and treated with hydrochloric acid (12.5 of concentrated hydrochloric acid diluted with 50 ml water). The mixture was diluted with 200 ml of toluene, and the aqueous phase was separated and extracted with 200 ml of toluene. The combined organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residual solids were recrystallized from heptane-ethyl acetate (9:1), to get colorless solids, 40.29 g. (78.4% yield) m.p. 126-128° C. The mother liquor after chromatography over 150 g. silica gel, elution with 1:1 heptane-toluene, and trituration of residual solids in hexanes gave additional product, 6.56 g. (12.8% yield, total 91% yield), m.p. 126-128° C. Mass Spec: m/z 328, 330, (M+). A sample for analysis was prepared by recrystallization from hexanes, m.p. 127-129° C. Analysis: Calculated for C18H17BrO, C, 65.55, H, 5.20, and Br 24.27%. Found, C, 65.60, H, 5.51, and Br 24.71%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1([NH:15][C:16]2[C:17](=[O:36])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[C:32]([F:35])[C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:23]=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:6]5[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:40][CH2:39][CH2:37][OH:38])[CH2:14][CH2:13]4)[C:17]3=[O:36])[C:33]([CH3:34])=[C:32]([F:35])[CH:31]=2)[CH2:30][CH2:29]1
Reactant: NCCO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3OCCCl)CC2)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3OCCNCCO)CC2)c1=O

Procedure:
The title compound was prepared from 3-[3-({1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 281c) and ethanolamine using a similar method to that described for Example 167f.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:35]=[CH:34][C:22]2[CH2:23][C:24]([C:27]3[N:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)([CH3:26])[O:25][C:21]=2[CH:20]=1.O[CH2:37][C@@H:38]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:35]=[CH:34][C:22]2[CH2:23][C:24]([C:27]3[N:32]=[CH:31][C:30]([O:33][CH2:39][C@@H:38]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])[CH3:37])=[CH:29][CH:28]=3)([CH3:26])[O:25][C:21]=2[CH:20]=1
Reactant: COCOc1ccc2c(c1)OC(C)(c1ccc(O)cn1)C2
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCOc1ccc2c(c1)OC(C)(c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of diisopropyl azodicarboxylate (1.9 M in toluene, 2.20 mL) was added dropwise to a solution of diastereomer of 6-(6-(methoxymethoxy)-2-methyl-2,3-dihydrobenzofuran-2-yl)pyridin-3-ol (shorter retention time, 800 mg), (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (976 mg), and triphenylphosphine (1100 mg) in toluene (20 mL) at ambient temperature. The mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (1100 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br-].C([O:10][C:11]([CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])C.[OH:33][C:34]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:35]=1[CH:36]=O>CO>[OH:33][C:34]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:35]=1[CH:36]=[CH:13][C:11]([OH:12])=[O:10]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C=CC(=O)O)c(O)c1
Reaction time: 3 h
Yield: 83.1 %

Procedure:
In a 100 mL flask, 2.00 g of potassium carbonate was added to 15 mL of methanol. In a 50 mL flask, 2.67 g (6.2 mmol) of ethoxycarbonylmethyl(triphenyl)phosphonium bromide and 945 mg (6.2 mmol) of 2-hydroxy-4-methoxybenzaldehyde were dissolved in 10 mL of methanol. The resultant was gradually added to a well-stirred potassium carbonate solution in a dropwise manner. After stirring the resultant for 3 hours, completion of reaction was confirmed by TLC. The resultant was filtered to exclude potassium carbonate and subjected to vacuum concentration. After the concentration, 50 mL of a 1 N sodium hydroxide aqueous solution was added thereto and the resultant was stirred for one hour. After reaction was completed, a reaction solution thus obtained was filtered to exclude triphenylphosphine oxide, and concentrated hydrochloric acid was added thereto in a dropwise manner to make the reaction solution an acidic solution. A precipitate thus produced was collected by filtration and washed with a small amount of chloroform, thereby obtaining 1.00 g of 2-hydroxy-4-methoxycinnamic acid. Then, in a 100 mL three-necked flask, 1.00 g (6.0 mmol) of 2-hydroxy-4-methoxycinnamic acid was dissolved in 40 mL of dehydrated tetrahydroxyfuran, and 1.41 g (7.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) was added thereto. After 30 minutes, 0.72 ml (7.2 mmol) of piperidine was added thereto. After reaction was completed, a reaction solution thus obtained was condensed and dissolved in water. The resulting solution was extracted with chloroform to obtain an extract. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution, 1 N hydrochloric acid and then saturated saline, and then washed with a small amount of chloroform, thereby obtaining 1.03 g of a compound represented by the following formula (14).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][S:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:30])=[O:29])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2)c1ccccc1
Yield: 57.6 %

Procedure:
Prepared from N2-(3-Cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 119) (200 mg, 0.72 mmol) and benzenesulfonyl chloride (139 mg, 0.78 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (174 mg, 58%), MS (ISP) m/e=420.3 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[OH:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)=[CH:11][CH:10]=1>C(O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[O:33][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(B(O)C(OC(B(O)c2ccc(OC)cc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COc1ccc(B(OCCN(C)C)C(OC(B(OCCN(C)C)c2ccc(OC)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
The entitled compound (51 mg) was obtained by allowing 22 mg of N,N-dimethylethanolamine to act on 85 mg of bis(4,4′-(p-methoxyphenyl-hydroxyboryl)benzyl) ether in 0.5 mL of ethanol.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[N:30]=[C:31]([CH3:34])[S:32][CH:33]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:28]=[C:27]([C:29]4[N:30]=[C:31]([CH3:34])[S:32][CH:33]=4)[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: Cc1nc(C(N)=NO)cs1
Product: CCc1ccc(C2CC(c3nc(-c4csc(C)n4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-methyl-1,3-thiazole-4-carboximidamide were reacted according to the General Method 1. Yield: 36 mg (40% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:17]=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cccnc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,3-dichloropyridine [C.A.S. 2402-77-9] (10 g, 67.57 mmol) in dry THF (200 ml) cooled at −78° C. under a nitrogen atmosphere, was added dropwise n-butyllithium (37.165 ml, 74 mmol, 2 M in hexanes). The resulting reaction mixture was stirred at −78° C. for 20 min. Then dry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min. stirring at −78° C., the mixture was allowed to warm to r.t., quenched with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by short open column chromatography (DCM as eluent). The desired product fractions were collected and concentrated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM/heptane up to 50% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D36 (4.15 g, 34.9%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>COCCOC.C(OCC)(=O)C>[CH3:32][N:20]1[C:21](=[O:22])[C:16]2[C:15]([CH3:25])=[CH:14][N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[C:17]=2[N:18]=[C:19]1[S:23][CH3:24]
Reactant: CI
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c(=O)n1C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Under argon gas, 7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.85 g) was dissolved in anhydrous DME (50 ml)anhydrous DMF (50 ml) and, under ice-cooling, 60% sodium hydride-oil (176 mg) was added in two installments. After 30 minutes of stirring, methyl iodide (681 mg) was added. Then, at room temperature, the mixture was stirred overnight. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; ethyl acetate: hexane=1:5.6-1:2.3) to provide the title compound (1.31 g).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:13][C:12]3[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:11]=3[O:10]2)[CH2:5]1)(=O)C.[ClH:23]>C(O)C>[ClH:23].[CH3:22][S:19]([NH:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:6]3([CH2:7][CH2:8][CH2:9][NH:4][CH2:5]3)[CH2:13][C:12]=2[CH:14]=1)(=[O:20])=[O:21]
Reactant: CC(=O)N1CCCC2(Cc3cc(NS(C)(=O)=O)ccc3O2)C1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)CC1(CCCNC1)O2

Procedure:
A solution of 3.6 g (11.09 mmole) of 1'-Acetyl-2,3-dihydro-5-methanesulfonamidospiro(benzofuran-2,3'-piperidine) in 100 mL ethanol was treated with 50 mL 6 N hydrochloric acid and heated to reflux for 18 hours. The reaction was concentrated to dryness and the residue crystallized from ethanol to give 2.77 g of products mp=243°-244° C. 1H NMR (DMSO) δ9.6 (brs, 1H), 9.4 (s, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.0 (dd, J=1.6, 8.5 Hz), 6.70 (d, J=8.5 Hz, 1H), 3.5-2.8 (m, 6H), 2.88 (s, 3H), 2.0-1.30 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH2:15]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[CH3:16]
Reactant: CCI
Reactant: CCc1cc(O)cc(CC)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(CC)c(C=O)c(CC)c1
Temperature: 50 °C
Yield: 89.5 %

Procedure:
To a solution of 0.30 g (1.68 mmol) 2,6-diethyl-4-hydroxy-benzaldehyde in 8 ml N,N-dimethylformamide in a pressure tube were added 0.16 ml (2.02 mmol) iodoethane and 0.35 g (2.52 mmol) potassium carbonate. The tube was sealed and the reaction mixture was heated at 50° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether, and washed sequentially with water and saturated brine. The phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 1:30) to afford 0.31 g (88%) of the title compound as a yellow oil. MS (ISP): 207.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:3]([F:18])=[C:4]([N:8]2[C:12]([O:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.FC1[C:26]([O:27]C)=CC=CC=1N.N([O-])=O.[Na+].[N-]=[N+]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[F:18][C:3]1[C:2]([O:27][CH3:26])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[C:12]([O:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[N:9]1
Reactant: COc1c(C(=O)O)nnn1-c1cccc(Cl)c1F
Reactant: COc1cccc(N)c1F
Agent: O=N[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cccc(-n2nnc(C(=O)O)c2OC)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-Chloro-2-fluorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid: To a solution of 2-fluoro-3-methoxyaniline (1 g, 7.09 mmol) in TFA (10 mL) and water (5 mL) at 0° C. was added an aq. solution of NaNO2 (0.733 g, 10.63 mmol) dropwise. The resulting mixture was stirred at 0° C. for 0.5 h and NaN3 (0.921 g, 14.17 mmol) was added portionwise. The reaction mixture was gradually warmed to rt and stirred for 4 h. The reaction was quenched with water (150 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with sodium phosphate solution (10%) and brine (50 mL), dried, and concentrated. The resulting brown oil was re-dissolved in DMSO (20 mL) and added t-butylpropiolate (1 mL) followed by K2CO3 (1 g), Cu(OAc)2 (0.2 g), and sodium ascorbate (100 mg). The resulting mixture was stirred at rt overnight. The reaction was quenched with water (200 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography to yield the desired product as brown oil. 1H NMR (400 MHz, CDCl3) δ 13.19 (br. s., 1H), 7.36-7.20 (m, 2H), 7.17-6.95 (m, 1H), 6.76 (td, J=8.1, 1.3 Hz, 1H), 3.91 (s, 3H), 1.74-1.49 (m, 10H). MS(ESI) m/z: 238.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([CH:37]1[CH2:39][CH2:38]1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH:37]1([N:29]2[C:10]3[C@@:9]4([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]4)[C:11]=3[C:18](=[O:19])[N:30]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:39][CH2:38]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Nc1ccccc1)C1CC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
Triethylamine (120 μL, 0.86 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo [2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 90 mg, 0.42 mmol) in 1,2-dichloroethane (1 mL) over 1 min. A solution of N-cyclopropyl-N′-phenyl-hydrazinecarboxylic acid tert-butyl ester (66 mg, 0.27 mmol) in 1,2-dichloroethane (4 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 90 min. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h. A further portion of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the mixture was heated in an oil bath at 100° C. for 2 h. The solvent was evaporated. Dichloromethane (30 mL) was added and the mixture was washed with 1:1 water/brine (10 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 25-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with dichloromethane and then petroleum ether. The residue was dried under high vacuum at 75° C. overnight to give (4S,7R)-1-cyclopropyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (35 mg, 43%) as a light yellow solid. APCI(+)-MS (M+H) 309.