Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:18])[C:15](N)=[CH:16][C:4]=2[S:3]1.Cl.N([O-])=O.[Na+].[C:24]([O-])(=O)[CH3:25].[Na+]>O.C1C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:18])[C:15]([C:25]3[CH:24]=[CH:13][CH:5]=[CH:4][CH:16]=3)=[CH:16][C:4]=2[S:3]1
Reactant: CCOC(=O)Cn1c(=O)sc2cc(N)c(Cl)cc21
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cn1c(=O)sc2cc(-c3ccccc3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-oxo-5-chloro-6-amino-3-benzothiazolineacetate (347.8 l g) and conc.hydrochloric acid (1040 ml) was stirred for 30 minutes at ambient temperature. After the resultant mixture was cooled to 2° C., a solution of sodium nitrite (88.3 g) in water (120 ml) was added dropwise thereto below 5° C. in the course of 40 minutes. The mixture was stirred for 20 minutes at 0° C. To the resultant mixture was added benzene (5.2 l) in the course of 30 minutes. After the reaction mixture was stirred for an hour and 40 minutes under ice-cooling, a solution of sodium acetate.3H2O (1.56 kg) in water (3.6 l) was added dropwise thereto under ice-cooling in the course of an hour. The mixture was stirred overnight at ambient temperature. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give a residue, which was recrystallized from ethanol to give ethyl 2-oxo-5-chloro-6-phenyl-3-benzothiazolineacetate (311.5 g).
Reaction SMILES: C(=O)([O-])N.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH2:45]([OH:49])[CH:46]([OH:48])[CH3:47]>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[O:49][CH2:45][CH:46]([OH:48])[CH3:47])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CC(O)CO
Agent: NC(=O)[O-]
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OCC(C)O)cc3)nc21

Procedure:
A carbamate formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 1,2-propanediol as the alcohol component. (24%, MS=453.2 (M+H))
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:29][O:30][C:31]1[CH:37]=[C:36]([C:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH:43]=2)[C:35]([N+:45]([O-:47])=[O:46])=[CH:34][C:32]=1[NH2:33].CC(O)CCC>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:37]=[C:36]([C:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH:39]=2)[C:35]([N+:45]([O-:47])=[O:46])=[CH:34][C:32]=1[NH:33][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cnn3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 65.6 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 152, 256 mg, 1.00 mmol), p-toluene sulphonic acid monohydrate (271 mg, 1.43 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) and 2-pentanol (12 mL) was heated at reflux for 4 h under an atmosphere of N2. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. This solution was purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Fractions containing the desired product were concentrated in vacuo to give a residue that was dissolved into hot DMF (10 mL). This solution was filtered and concentrated in vacuo to provide a gum that was triturated with CH3CN (10 mL) to give the title compound (285 mg, 66%) as a yellow powder; 1H NMR: 2.36 (5H, s), 2.67 (2H, s), 3.07 (2H, s), 4.02 (3H, s), 5.66 (1H, s), 7.00 (1H, s), 7.12 (1H, t), 7.41 (1H, m), 7.45 (1H, m), 8.45 (2H, t), 8.59 (1H, d), 8.83 (2H, t), 8.90 (1H, s); m/z: ES− M-H− 456.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]2=[O:18])=[CH:7][N:6]=1)=O.CO.[BH4-].[Na+]>C(Cl)Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:12](=[O:18])[N:11]([C:8]2[CH:7]=[N:6][C:5]([CH2:3][OH:2])=[CH:10][N:9]=2)[CH:16]=1
Reactant: COC(=O)c1cnc(-n2cc(Cl)ccc2=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=c1ccc(Cl)cn1-c1cnc(CO)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the ester from step 2 (1.41 g, 5.317 mmol), in CH2Cl2 and methanol (1:1 50 ml) at 0° C. was treated with sodium borohydride (2.01 g, 53.17 mmol) and the reaction was stirred at room temperature for 18 hrs. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc and the combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 2:98 to 5:95 gradient elution) to afford the title compound.
Reaction SMILES: C1(CC([O:10][C:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13](=[O:27])[CH:12]=2)=O)CCCCC1.C(N([CH2:33][CH3:34])CC)C.[C-]#N.[K+].C1[O:55][CH2:54][CH2:53]OCCOCCOCCOCCOC1>ClCCl.C1(C)C=CC=CC=1>[CH:34]1([CH2:53][C:54]([C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15]3[C:20]([C:11]=2[OH:10])=[CH:19][CH:18]=[CH:17][N:16]=3)=[O:55])[CH2:33][CH2:13][CH2:12][CH2:11][CH2:20]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(CC1CCCCC1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Reactant: CCN(CC)CC
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(CC1CCCCC1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dry toluene (30 mL) was added to 4-cyclohexylacetoxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1.31 g, 3.61 mmol), triethylamine (0.50 mL, 3.61 mmol, 1 eq.), potassium cyanide (472 mg, 7.24 mmol, 2 eq.), and 18-crown-6 (190 mg), and the mixtures was stirred at a room temperature for 2 days. Dichloromethane was added thereto. The mixture was filtered by using Celite, and then the solvent was distilled off. The resulting residue was purified by a flash column chromatography to give an objective 3-cyclohexylacetyl-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one as a form of crystal (625 mg, yield 48%).
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[F-:6].[Cl-:7].[NH3:8].[Mg:9]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[NH4+:8].[Mg+2:9].[F-:6].[Mg+2:9].[F-:6].[Cl-:7].[Mg+2:9].[Cl-:7]
Reactant: [Mg]
Reactant: N
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [F-]
Product: [Mg+2]
Product: [NH4+]

Procedure:
phosphate and fluoride or chloride ions and buffered with ammonia or an amine to a pH of about 5 to 11, applying a direct current to the bath, and pulsing the direct current, whereby on the surface of the magnesium or its alloy there is formed magnesium ammonium phosphate and magnesium fluoride or magnesium chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[Si:27]([O:34][CH:35]([C:37]1[CH:38]=[C:39]2[C:44](=[N:45][C:46]=1[CH:47]([O:50][CH3:51])[O:48][CH3:49])[NH:43][CH2:42][CH2:41][CH2:40]2)[CH3:36])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[Si:27]([O:34][CH:35]([C:37]1[CH:38]=[C:39]2[C:44](=[N:45][C:46]=1[CH:47]([O:50][CH3:51])[O:48][CH3:49])[N:43]([C:20]([NH:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[O:21])[CH2:42][CH2:41][CH2:40]2)[CH3:36])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1C(C)O[Si](C)(C)C(C)(C)C)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)O[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 524 mg, 2.73 mmol) in DMF (1.5 mL) was added drop wise to a cooled suspension of di(1H-1,2,4-triazol-1-yl)methanone (448 mg, 2.73 mmol) in DMF (1.5 mL) at 0° C. The reaction mixture was stirred for 3 h at 0° C., after which it was allowed to warm to room temperature. A solution of (racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 185, 500 mg, 1.364 mmol) in DMF (2.0 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (100 mL) and solid precipitates were filtered off. Solvents were concentrated and the crude material was purified by silica gel column chromatography eluting with a gradient of MeOH (0-4%) in DCM, followed by re-purification with a gradient of EtOAc (0-40%) in heptane. Fractions containing the product were combined to yield the title compound as a waxy solid. (UPLC-MS 3) tR 1.66 min, ESI-MS 585.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:13]=[C:12]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[S:11]1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([O-:39])=[O:38].[NH2:7][CH2:8][CH2:9][C:10]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:11][C:12]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[N:13][N:14]1[C:15](=[O:20])[C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCN)(c2ccccc2)S1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
{2-[3-(2,2-Dimethylpropionyl)-5-(2,2-dimethylpropionylamino)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}carbamic acid tert-butyl ester (274 mg, 0.557 mmol) obtained in Step 2 mentioned above was dissolved in dichloromethane (10 mL). To the resulting solution was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added diisopropyl ether, and the mixture was stirred for 3 hours. The deposited white solid was collected by filtration to give trifluoroacetate of N-[5-(2-aminoethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (252 mg, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH2:25]([NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:26]>>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:27]([CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH2:25][CH3:26]
Reactant: CCNCCN(C)C
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CCN(CCN(C)C)Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and N′-ethyl-N,N-dimethyl-ethane-1,2-diamine to give a yellow solid. MS m/z: 434.2 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]([CH:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22]=1[CH2:23][CH3:24])=[O:17])[CH3:14])#[N:12].C([O-])(=O)C.[Na+]>ClC(Cl)C>[C:11]([CH:13]([O:15][C:16]([C:18]1[NH:19][C:20]([CH:8]=[O:9])=[C:21]([CH2:25][CH3:26])[C:22]=1[CH2:23][CH3:24])=[O:17])[CH3:14])#[N:12]
Reactant: CCc1c[nH]c(C(=O)OC(C)C#N)c1CC
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1c(C=O)[nH]c(C(=O)OC(C)C#N)c1CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
15 ml (160 mmol) phosphorous oxychloride were added dropwise for a period of 20 minutes to 13 ml (160 mmol) dimethylformamide at a temperature of 0° C. The mixture was stirred for another 15 minutes at room temperature and then 100 ml of dichloroethane were added. A solution of 10 g (40 mmol) of compound 11 in 50 ml dichloroethane were added dropwise. After gentle reflux for 15 minutes, the mixture was poured into 500 ml of a 4-molar sodium acetate solution and heated for a further 15 minutes. The organic layer was separated, washed with water and yielded after evaporation of the solvent, a brown oil, which was directly used for the next step without purification.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].N(OC(C)(C)C)=O.N[C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>C(O)(=O)C>[C:1]([O:4][C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC[C@H](N)C(=O)O
Reactant: CC(=O)[O-]
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@H](OC(C)=O)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Sodium acetate (11.9 g, 146 mmol) and tert-butyl nitrite (15.0 g, 146 mmol) were added to an acetic acid (300 mL) solution of (2S)-2-aminobutyric acid (10.0 g, 97.0 mmol) under ice cooling, and was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with water and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, further the residue was azeotropically boiled with 1,4-dioxane (50 mL) twice. Thus, the title compound (8.4 g, yield: 60%) was obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:18]=2)=[O:21])=[CH:29]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-(3-trifluoromethyl-phenyl)-methanone was prepared from phenanthridine, 3-trifluoromethylbenzoyl chloride, and indole according to GP 2. Yield, 3%. 1H-NMR (DMSO-d6): δ=6.24 (d, J=1.9 Hz, 1H), 6.38 (s, br., 1H), 6.82 (t, J=7.5 Hz, 1H), 7.01-7.10 (m, 2H), 7.15 (t, J=7.6 Hz, 1H), 7.20-7.32 (m, 2H), 7.40-7.60 (m, 6H), 7.74 (d, J=7.3 Hz, 1H), 7.88 (d, br., J=7 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 10.73 (s, 1H); (+)-ESI-MS: m/z=469 [M+H]+, 352 [M-indole+H]+; (−)-ESI-MS: m/z=467 (M−H)−.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C1(C)C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([C:32](=O)[CH2:33][CH3:34])[CH:28]=[C:29]([F:31])[CH:30]=1>C(OCC)(=O)C>[F:24][C:25]1[CH:26]=[C:27]([C:32]2([CH2:33][CH3:34])[O:4][CH2:1][CH2:2][O:3]2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CCC(=O)c1cc(F)cc(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(c2cc(F)cc(F)c2)OCCO1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Ethylene glycol (773 mg) and a catalytic amount of tosylic acid monohydrate were added to a toluene (20 ml) solution of 1-(3,5-difluorophenyl)propan-1-one (1.06 g). A Dean-Stark tube was attached to the reactor, the reaction liquid was stirred overnight with heating under reflux, then diluted with ethyl acetate, and washed with aqueous saturated sodium hydrogencarbonate solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain the entitled compound (1.31 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH3:23].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH3:23]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.25 g (7.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.35 g (7.0 mmol) of acetaldehyde in 30 ml of ethanol, 0.07 ml (0.7 mmol) of piperidine was added, followed by refluxing for 5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/2) to yield 0.48 g (19.7%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:16]([CH2:18][S:19](Cl)(=[O:21])=[O:20])#[N:17].[OH-].[Na+]>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:19]([CH2:18][C:16]#[N:17])(=[O:21])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: N#CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(NS(=O)(=O)CC#N)cc1
Yield: 18.2 %

Procedure:
To a solution of para-anisidine (1.95 g) in acetonitrile (25 ml) at 15° C. under argon atmosphere was added pyridine (1.25 g), then cyanomethanesulfonyl chloride (2 g) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml water and the pH was made basic by addition of 1N aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate, then concentrated in vacuo. Column chromatography (ethyl acetate/cyclohexane 1:1) afforded the title product as an orange solid (590 mg). 1HNMR (CDCl3, 400 MHz): 7.30 (d, 2H), 6.95 (d, 2H), 6.70 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O)[CH3:12].C[Si](C)(C)[N-:26][Si](C)(C)C.[Li+].B(F)(F)F.CCOCC>O1CCCC1.CCCCCC.CCOCC>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:17]([NH2:26])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CS(C)(=O)=O
Reactant: CCOc1cc(C=O)ccc1OC
Agent: FB(F)F
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Temperature: 78 °C
Reaction time: 0.42 h
Yield: 38.7 %

Procedure:
To a stirred solution of dimethyl sulfone (3.70 g, 39.4 mmol) in tetrahydrofuran (350 mL), was added n-butyllithium (17.5 mL, 2.5 M, 43.8 mmol) under nitrogen at -78° C. and the mixture was stirred at 78° C. for 25 min. To a stirred solution of 3-ethoxy-4-methoxybenzaldehyde (7.10 g, 39.4 mmol) in tetrahydrofuran (40 mL) under nitrogen in a separate flask at 0° C. was added lithium hexamethyldisilazide (43.0 mL, 1.0 M, 43.0 mmol) in hexane. After 15 min, boron trifluoride etherate (10.0 mL, 78.9 mmol) was added to the resulting mixture at 0° C. After 5 min, this solution was added to the -78° C. sulfone solution via syringe. The solution was allowed to warm to room temperature over one hour. The resulting mixture was then quenched with potassium carbonate (32 g) and water (200 mL). The mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), and then dried over magnesium sulfate. The solvent was removed in vacuo and the resulting solid stirred with ether (100 mL) and 4 N hydrochloric acid (100 mL) for 15 min. The aqueous layer was separated and the organic layer extracted with 4 N hydrochloric acid (30 mL). The combined aqueous layers were washed with ether (50 mL), stirred, and cooled in an ice bath and the pH adjusted to 14 with sodium hydroxide (5 N). This solution was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium carbonate and sodium sulfate. Removal of solvent in vacuo gave an oil which was stirred with ether (20 mL) for 20 min to give a suspension. The suspension was filtered and the solid was washed with ether (20 mL) and then dried in a vacuum oven to yield 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine as an off-white solid (4.17 g, 39%): mp, 116.5-117.0° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7 Hz, 3H, CH3), 1.92 (br s 2H, NH2), 2.91 (s, 3H, SO2CH3), 3.19 (dd, J=3.5, 14 Hz, 1H, CHH), 3.36 (dd, J=9.3, 14 Hz 1H, CHH), 3.87 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.60 (dd, J=3.5, 9 Hz, 1H, CH), 6.83-6.93 (m, 3H, Ar); 13C NMR (CDCl3) δ 14.75, 42.42, 50.94, 55.99, 63.18, 64.44, 110.71, 111.67, 118.21, 135.55, 148.72, 149.09; Anal Calcd for C12H19NO4S: C, 52.73; H, 7.01; N, 5.12. Found: C, 52.82; H, 6.69; N, 4.99.
Reaction SMILES: S(O[C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[CH:18]([OH:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N+:28]([O-])=O)(C(F)(F)F)(=O)=O.C(N(CC)CC)C.ClCCl>CO.[Pd]>[NH2:28][C:10]1[C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=[CH:26][CH:9]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]1[OH:27]
Reactant: C[C@]12CC[C@@H]3c4ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c4CC[C@H]3[C@@H]1CCC2O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C[C@]12CC[C@@H]3c4cccc(N)c4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 5 h
Yield: 25 %

Procedure:
A solution of 4-nitroestra-1,3,5(10)-trien-3,17-diol 3-O-triflate (2.13 g, 4.74 mmol) in 100 ml of methanol containing triethylamine (6.60 , 4.8 mmol) and 10% Pd/C (430 mg. 20% by weight) was hydrogenated in a Parr apparatus at 16 psi for 5 hr. TLC using 95% dichlormethane 1% methanol showed one major product and 3 minor constituents. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was dissolved in excess dichloromethane and the solution was washed with water. The extract was dried over sodium sulfate and filtered. The filtrate was evaporated to dryness. The residue crystallized from methanol as a cluster of colorless needles of 4-aminoestra-1,3,5(10)-trien-17β-ol; wt. 320 mg. (25% yield), mp 189°-192° C. Mass Spectrum: m/z 271 (M+), 237 (M--H2O+NH2). 1H NMR 7.23-6.51 (m, 3, H1, H2, H3 aromatic) 3.71-3.45 (t, 1, 17H), 2.57-1.23 (m, 18), 0.876 (s, 3, C18CH3).