Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Product: CC(C)c1nn2ccccc2c1-c1cccnc1

Procedure:
2-Isopropyl-3-pyridin-3-yl-pyrazolo[1,5-a]pyridine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 3-pyridineboronic acid following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example 59) (240 mg, 32%). 1H-NMR (250 MHz, DMSO-d6) δ 8.69 (d, J=7.3 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J=4.0 Hz 1H), 7.85 (d, J=7.8 Hz, 2H); 7.56-7.47 (m, 1H), 7.20 (t, J=8.8 Hz, 1H), 6.89 (t, J=6.8 Hz, 1H), 3.24 (sept, J=7.0 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H); LC/MS 237.9 m/z (M+H+). Compound 1111.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13]C)[CH:12]=1)[C:9](=[O:15])[N:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.[Li+].[Cl-]>>[OH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[C:9](=[O:15])[N:8]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(-n2ccc3cc(OC)cc(OC)c3c2=O)cc1
Agent: [Cl-]
Agent: [Li+]
Product: COc1ccc(-n2ccc3cc(OC)cc(O)c3c2=O)cc1
Temperature: 140 °C
Yield: 83.7 %

Procedure:
6,8-Dimethoxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (2.25 g, 7.23 mmol) and LiCl (6.12 g, 144.54 mmol) were placed in a dry, argon flushed 150 mL three-necked flask fitted with a stirring bar and reflux condenser. Anhydrous DMF (30 mL) was added via a syringe. The reaction mixture was heated to 140° C. under vacuum for 20 h. Then, the reaction was quenched by addition of 30 mL of 2N HCl solution. The solution was extracted with EtOAc (3×30 mL). The extracts were combined and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica-gel, EtOAc) to give a white solid product, 1.80 g, 83.7% yield. 1H NMR (DMSO-d6, 300 MHz): δ 12.98 (s, 1H), 7.42-7.35 (m, 3H), 7.06 (d, 2H, J=9.0 Hz), 6.70-6.67 (m, 2H), 6.45 (d, 1H, J=2.1 Hz), 3.85 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:28]>ClCl>[NH2:28][CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: N
Reactant: COc1nc(Cl)ccc1CCO
Agent: ClCl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COc1nc(Cl)ccc1CCN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.20 g (0.8 mmol) of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine in 10 ml of dry CH2 Cl2 cooled to -50° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for 30 min at this temperature and an additional 10 min at -78° C. before a rapid addition of 30 ml of cold (-78° C.) NH3 (1). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford 1.0 g of crude 3-(2-aminoethyl)-6-chloro-2-methoxypyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Br[CH2:8][C:9]([C:11]1[S:12][C:13]([CH3:22])=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][C:15]=12)=[O:10]>CC(C)=O>[O:4]([CH2:8][C:9]([C:11]1[S:12][C:13]([CH3:22])=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][C:15]=12)=[O:10])[C:1]1[CH:14]=[CH:15][CH:11]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1sc(C(=O)CBr)c2c1CC(C)(C)CC2
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1sc(C(=O)COc2ccccc2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the appropriate phenols (50 μmol, 2 eq.) and K2CO3 (10.5 mg, 75 μmol) a solution of 2-bromo-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (7.5 mg, 25 μmol) in acetone (0.7 mL) is added. The suspension is stirred at rt for 18 h before it is filtered. The solvent of the filtrate is evaporated and the crude product is purified by prep. HPLC (Symmetry C18 5 μm, 19×50 mm, 20-95% acetonitrile in water containing 0.5% formic acid) to give the desired 2-phenoxy-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:46]([C:69]([F:72])([F:71])[F:70])=[N:47][N:48]([C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([C:69]([F:70])([F:72])[F:71])=[N:47][N:48]([C:50]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-(trifluoromethyl)-1-trityl-1H-pyrazole and used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:9]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])#[CH:10]>ClCCl>[C:9]([C:11]1[CH:12]=[C:13]([NH:14][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[CH:15]=[CH:16][CH:17]=1)#[CH:10]
Reactant: O=C1CCCC(=O)O1
Reactant: C#Cc1cccc(N)c1
Solvent: ClCCl
Product: C#Cc1cccc(NC(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
Glutaric anhydride (215 mg, 1.9 mmol) was dissolved in anhydrous dichloromethane (7 ml) and followed by the addition of 3-ethynylaniline (200 mg, 1.7 mmol). The mixture was allowed to stir at room temperature for 6 hours before the solvent was evaporated under reduced pressure to provide the product as a white solid (363 mg, 99%);
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:25][OH:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:43](O)(=[O:45])[CH3:44].C(=O)([O-])O.[Na+]>O1CCCC1.O>[C:43]([O:26][CH2:25][C:10]1[C:11]2[C:12](=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:27])(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: Cc1c(CO)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccccc3)nncc12

Procedure:
A solution of 1.65 g (4.59 mmol) of 1-benzyl-7-benzyloxy-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 3.8 g (18.6 mmol) of dicyclohexylcarbodiimide and 1.6 ml (27.4 mmol) of glacial acetic acid in 50 ml of anhydrous tetrahydrofuran is stirred at room temperature for 18 h. The solution is then treated with 50 ml of water, rendered neutral with saturated sodiumhydrogen carbonate solution and extracted with 3×50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: ethyl acetate). After crystallization from diisopropyl ether, 1.3 g (71%) of the title compound are isolated. M.p.: 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:11][CH2:10]/[CH:9]=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC/C=C/c1ccccc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccccc1/C=C/COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (E)-3-(2-chlorophenyl) prop-2-en-1-ol(Preparation example 1, 5.3 g, 31.6 mmole) in THF was added NaH (60% in mineral oil, 0.91 g, 37.7 mmole) and Benzyl bromide (4.12 mL, 34.8 mmole), sequently at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (4.94 g, 70˜90%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
4-Chloro-2-nitroaniline (40 g, 0.23 mol) was dissolved in 12N hydrochloric acid (100 ml). At 0° C., sodium nitrate (16 g, 0.23 mol) dissolved in water (50 ml) was slowly added in drops thereto, and the mixture was stirred for 30 min at 0° C.˜room temperature. The temperature was lowered to 0° C., and tin(II) chloride (132 g, 0.70 mol) dissolved in 12N hydrochloric acid (100 ml) was slowly added in drops thereto. The mixture was stirred for 3 h at 0° C.˜room temperature. The resulting yellow solid was filtered, washed with a small quantity of 6N HCl, and dried to give the title compound (30 g, Yield 63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccccc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 72.5 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.16 g of 2-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-fluorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (34)).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=O.Cl>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:10]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Methyl thioglycolate (19.62 mL, 0.216 mol) was added dropwise, via syringe pump, to a stirred suspension of 95% sodium hydride (5.99 g, 0.237 mol) in dry N,N-dimethyl-formamide (400 mL) at r.t. under nitrogen (CAUTION: hydrogen evolution). Upon complete addition, the reaction was stirred for 10 min and then a solution of 2-chloro-5-nitrobenzaldehyde (40.0 g, 0.216 mol) in DMF (120 mL) was added. The solution turned orange and a gentle exotherm was observed. After 1h, the now yellow mixture was heated to 100° C. for 5 h. The mixture turned amber in appearance. After cooling to r.t. the mixture was poured into 1 N aqueous hydrochloric acid (500 mL). The resulting yellow precipitate was filtered off and washed with water (250 mL). The solid was suspended in hot methanol/ethyl acetate (1:1) (1000 mL) and allowed to cool to r.t. The resulting solid was filtered off and air dried to yield methyl 5-nitrobenzo[b]thiophene-2-carboxylate (33.77 g, 66%) as a tan amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 3.92 (s, 3H), 8.32 (dd, J=9, 2 Hz, 1H), 8.37 (d, J=9 Hz, 1H), 8.45 (s, 1H), 9.00 (d, J=2 Hz, 1H).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH3:46][O:47][CH2:48][CH2:49]NC>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]([CH2:49][CH2:48][O:47][CH3:46])[CH3:6])=[O:38])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: CNCCOC
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: COCCN(C)C(=O)c1cc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (150 mg) described in Example 769 and (2-methoxyethyl)(methyl)amine (108 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (58 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.O[C:14]([C:17](O)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]2[O:9][C:17]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:15])[O:10]2)[CH:7]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Yield: 57 %

Procedure:
The title compound (57%, oil) was prepared from 5-chloro-2-methoxyphenylboronic acid and pinacol.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.[OH-].[Na+]>CN(C=O)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium hydride (2.40 g, 60 mmol) (60% by wt) was weighed into a flask and washed with several hexane rinsings. The hexanes were decanted and discarded and 20 mL DMF was added to the flask. A DMF-solution of benzenethiol (5.1 mL, 50 mmol in 50 mL DMF) was added dropwise to the NaH mixture and stirred at room temperature. To 4-bromo-2-fluoro-benzonitrile (10.0 g, 50 mmol) in 40 mL DMF) was added benzenethiophenoxide (described above), dropwise, over 30 minutes. Upon complete addition, the reaction was stirred at room temperature for 20 min. At that time, the mixture was poured into cold 1 N NaOH. A precipitate formed and was collected by vacuum filtration to give 14.0 g (48.4 mmol) of Compound 1h.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].Cl.[CH3:15][C:16]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH2:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH:22][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1
Reactant: CC1(C)CCCC1CN
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)CCCC1CNC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of 4-formylcinnamic acid (345 mg, 1.96 mmol) and 2,2-dimethylcyclopentylmethylamine, hydrochloride (321 mg, 1.96 mmol; title B compound of Example 1) in DMF (5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (954 mg, 2.16 mmol) and N-methylmorpholine (0.47 mL, 4.31 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl and saturated NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated in vacuo to yield a light amber gum. MS: (ESI), (M+H)+ 286.
Reaction SMILES: [Br-].C(NCCCCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=O)CCCCC.C([O:44][C:45]1[CH:62]=[CH:61][C:60]2[C@@H:59]3[C@H:50]([C@H:51]4[C@@:55]([CH2:57][CH2:58]3)([CH3:56])[C@@H:54]([OH:63])[CH2:53][CH2:52]4)[C@H:49]([CH:64]=[CH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74](=[O:80])[CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH2:48][C:47]=2[CH:46]=1)C1C=CC=CC=1>>[OH:44][C:45]1[CH:62]=[CH:61][C:60]2[C@@H:59]3[C@H:50]([C@H:51]4[C@@:55]([CH2:57][CH2:58]3)([CH3:56])[C@@H:54]([OH:63])[CH2:53][CH2:52]4)[C@H:49]([CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74](=[O:80])[CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH2:48][C:47]=2[CH:46]=1
Reactant: CCCCCC(=O)NCCCCCCCC=C[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CCCCCC(=O)NCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCC(=O)NCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in the last paragraph of Example 6 was repeated except that (8-hexanamidooctyl)triphenylphosphonium bromide was used in place of (9-carboxynonyl)triphenylphosphonium bromide. The hydrogenation process described in the second paragraph of Example 6 was then repeated using the N-[9-(3-benzyloxy-17β-hydroxyoestra-1,3,5(10)-trien-7α-yl)non-8-enyl]hexanamide thus obtained as starting material, and there was thus obtained as an oil N-[9-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)nonyl]hexanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]2[S:12][CH:13]=[CH:14][C:5]=2[N:4]=1.CN(C)C=[O:18].[OH-].[Na+]>O1CCOCC1>[N:8]1[CH:9]=[N:10][N:11]2[C:7]=1[C:6]1[S:12][CH:13]=[CH:14][C:5]=1[NH:4][C:3](=[O:18])[CH2:2]2
Reactant: ClCc1nc2ccsc2c2nncn12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1Cn2ncnc2-c2sccc2N1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
5. 15.2 g of 5-(chloromethyl)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine are suspended in 650 ml of dioxan and 43 ml of dimethylformamide and cooled to 5° C. 86 ml of 1N sodium hydroxide solution are added thereto within 3 min. and the mixture is stirred at room temperature for 17 h. The reaction mixture is then partitioned between 1.5 l of saturated aqueous sodium chloride solution and 0.7 l of chloroform. The aqueous phase is then made weakly acidic (pH 6) with 12N hydrochloric acid. The mixture is extracted five times with chloroform. The organic extracts are concentrated in a vacuum. The crystalline residue is recrystallized from ethanol. There is obtained 5H-thieno[2,3-f][1,2,4]triazolo[1,5-d][1,4]diazepin-6(7H)-one of m.p. 213°-215° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: BrCC1CO1
Product: O=S(=O)(c1ccc(OCC2CO2)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Reaction of 2-(4-hydroxyphenylsulfonyl)-3-phenylbenzofuran with epibromohydrin according to the procedure of Example 3 gives 2-[4-(2,3-epoxypropoxy)phenylsulfonyl]-3-phenylbenzofuran.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1.[F:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][C:19]=1[CH:20]=[O:21]>C1COCC1>[F:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[C:11]([CH:20]([C:19]2[CH:22]=[C:23]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:18]=2[F:17])[OH:21])[CH:10]=[CH:9][N:8]=1
Reactant: COCOc1cccnc1F
Reactant: O=Cc1cc(-c2cccnc2F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1c(C(O)c2cc(-c3cccnc3F)ccc2F)ccnc1F
Reaction time: 1 h
Yield: 68.3 %

Procedure:
DIPA (3.5 mL, 24.97 mmol) was dissolved in dry THF (10 mL) under nitrogen and cooled in a dry ice bath. Butyllithium solution (2.5 m in hexanes, 10.0 mL, 25.00 mmol) was added and after stirring for a few minutes 2-fluoro-3-(methoxymethoxy)pyridine (3.71 g, 23.64 mmol) in dry THF (25 mL) was added dropwise. The reaction was stirred for 1 h. A solution of 2-fluoro-5-(2-fluoropyridin-3-yl)benzaldehyde (4.71 g, 21.49 mmol) in dry THF (40 mL) was added dropwise over 10 min. The reaction was removed from the cold bath and stirred for an additional 15 min. Saturated sodium bicarbonate (20 mL) was added followed by EtOAc (300 mL) and water (400 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (2-fluoro-3-(methoxymethoxy)pyridin-4-yl)(2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (5.52 g, 14.67 mmol). MS m/z=377.1 [M+H]+. Calculated for C19H15F3N2O3: 376.10.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 78.6 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.