Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C[CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#N.[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[O:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[O:9][CH2:4][CH:5]1[CH2:15][C:14]([OH:17])=[O:16]
Reactant: CC(=O)O
Reactant: N#CCC1COc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC1COc2ccccc2O1

Procedure:
A mixture of 175 g 2-cyanomethyl 1,4-benzodioxan, 250 ml water, 250 ml acetic acid and 100 ml concentrated sulphuric acid are heated to reflux for 48 hours. The reaction mixture is then poured in 5000 ml water and the whole is kept under stirring. The thus found crystalls are filtered, washed with water and dried, giving rise to 172 g (1,4-benzodioxan-2yl)acetic acid melting at 95°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:7][O:8][CH3:9])[CH2:6]O1.[S-:10]C#N.[K+]>O>[CH3:1][O:2][CH2:3][C:4]1([CH2:7][O:8][CH3:9])[CH2:6][S:10]1
Reactant: N#C[S-]
Reactant: COCC1(COC)CO1
Agent: [K+]
Solvent: O
Product: COCC1(COC)CS1
Reaction time: 6 h
Yield: 89.2 %

Procedure:
2,2-Bis(methoxymethyl)oxirane (13 g) was stirred with a solution of potassium thiocyanate (9.7 g) in water (40 cm3) for 18 h at room temperature. The aqueous layer was then replaced with a fresh solution of potassium thiocyanate (9.7 g) in water (40 cm3) and the mixture stirred for a further 6 h. The bulk of the thiirane was then separated from the aqueous layer which was then extracted with diethyl ether. These extracts were combined with the bulk of the thiirane, the solution dried and the solvent removed (40° C. at 15 mmHg) to give the thiirane (13 g, 90%) as a colourless liquid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:24]([O:26][C:27]1[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][NH:29][N:28]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27]1[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][N:29]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:28]=1)[CH3:25]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Sodium hydride (60%, oily, 39.4 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (300 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (195 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (364 mg, yield 79%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[C:17](Br)=[N:18][CH:19]=[CH:20][CH:21]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([OH:15])[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2Br)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2)CC1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of the above alcohol (470 mg, 1.27 mmol) in MeOH (4 ml) in a Parr flask was added 10% Pd/C (80 mg) under N2. The mixture was hydrogenated at room temperature under 1.5 atm H2 for 1 h. 3N NaOH (5 mL) was added and the mixture was extracted with CHCl3 (20 mL×2). The combined organic solution was filtered through a short pad of Celite® to give 4-(hydroxy-pyridin-3-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester (270 mg, 72%) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1C#N
Reaction time: 8 h
Yield: 53.7 %

Procedure:
2-Bromo-5-trifluoromethylbenzonitrile (2.5 g.; prepared as described by M. Gordon, I. J. Pachter and J. W. Wilson, Arzneimittel-Forsch., 1963, 13, 802) and a solution of sodium methoxide (prepared from 0.5 g. sodium and 20 ml. anhydrous methanol) were stirred and refluxed together for 4 hours, and allowed to stand at room temperature overnight. The methanol was evaporated and the residue was acidified with 2N hydrochloric acid, with cooling. The mixture was extracted with diethyl ether, and the extract was dried over anhydrous sodium sulphate, filtered and the filtrate was evaporated, and the residue was recrystallised from pentane to give 2-methoxy-5-trifluoromethylbenzonitrile (1.0g.), m.p. 31°-33° C.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[O:36])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Product: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](NC(=O)C4CCOCC4)CC3)CC2)n1

Procedure:
The title compound, off-white solid (128 mg, 94%), MS (ISP) m/z=455.4 [(M+H)+], mp 219° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC(=O)C)(=O)C>>[Br:1][C:2]1[C:3]([C:8]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1Br
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ncccc1Br

Procedure:
3-Bromopicolinamide, prepared as in Example 2(4 g.) is heated with 100 ml. of acetic anhydride on a steam bath. The mixture is then concentrated and worked up by diluting and triturating with water. The solid is dried and sublimed to give 3-bromopicolinonitrile.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1>>[C:5]1([C:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:13])[S:1][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1CCCC(=O)O1
Reactant: c1ccsc1
Product: O=C(O)CCCC(=O)c1cccs1
Temperature: 60 °C

Procedure:
Thiophene (19.5 ml) and glutaric anhydride (27.5 g) were mixed and heated to 60° C. under a nitrogen atmosphere until all solid dissolved. The heat was removed and 2.4 grams of 85% orthophosphoric acid was added. The reaction mixture was then heated to 100° C. for four hours, cooled, and 46 ml of water added. The mixture was extracted with ether then the ether phase was extracted with aqueous sodium hydroxide solution (2.5N). The aqueous phase was cooled and made acidic by addition of 6N hydrochloric acid. Solid which precipitated out was collected on a filter, washed with water and dried under vacuum at 60° C. Yield 9.2 g N.M.R. (CDCl3)δ2.1 (m, 2H), 2.54 (t, 2H), 3.04 (t, 2H), 7.14 (t, 1H), 7.64 (dd, 1H), 7.74 (d, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:30])([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[NH:25][O:26][C:27](=[O:29])[N:28]=2)[CH:19]=1)[C:14]([F:17])([F:16])[F:15].[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[N:31]1([C:36]([N:28]2[C:27](=[O:29])[O:26][N:25]=[C:24]2[C:20]2[CH:19]=[C:18]([C:13]([F:12])([F:30])[C:14]([F:15])([F:17])[F:16])[CH:23]=[CH:22][N:21]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=c1nc(-c2cc(C(F)(F)C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(Cl)N1CCCC1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)C(F)(F)F)ccn2)noc1=O
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To 2 ml of pyridine were added 0.16 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.14 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-(1-pyrrolidinecarbonyl)-3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (63)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])[CH3:20].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][CH2:19][CH3:20])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1C(=O)Nc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 71.6 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 528 mg (2.11 mmol) was added at 0° C. to a solution of 2-ethoxybenzoic acid chloride 390 mg (2.11 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then for 72 h at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 600 mg (1.51 mmol, 72% of theoretical) was obtained.
Reaction SMILES: N[CH:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH:12]([CH2:17][C:18]([O:20]C)=[O:19])[C:13]([O:15]C)=[O:14])[CH:5]=[N:4][C:3]1=2.C(O)(=[O:24])C.N([O-])=O.[Na+].C(OCC)C>O>[O:24]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH:12]([C:13]([OH:15])=[O:14])[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[N:4][C:3]1=2
Reactant: COC(=O)CC(Cn1cnc2c1N=CNC2N)C(=O)OC
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CC(Cn1cnc2c(=O)[nH]cnc21)C(=O)O
Yield: 31 %

Procedure:
2.00 g (6.82 mmol) of 2-[(1,6-dihydro-6-amino-9H-purin-9-yl)methyl]butanedioic acid, dimethyl ester (AIT-0073) was placed into a 50 ml round bottom flask equipped with a magnetic stirring bar. Then 10 ml glacial acetic acid was added and the solution was stirred until homogeneous. 2.35 g (34.10 mmol) of NaNO2 in 4 ml of H2O was added to the stirring solution dropwise. The stoppered solution was stirred for 24 hours at room temperature. An additional 0.775 g (11.23 mmol) of NaNO2 in 1 ml H2O was added and the solution was stirred for another 24 hours. The acetic acid was removed under reduced pressure on the rotary evaporator. Water was added and was removed in the same manner. This was repeated again until little or no more acetic acid was left. 10 ml of H2O was added to the semi-solid residue to completely dissolve the mixture. This solution was extracted with 30 ml-40 ml of acetonitrile and the aqueous layer was discarded. The organic layer was washed twice with 30 ml of saturated brine. Upon evaporation of the solvent, a light orange oil was obtained. This was treated with 35 ml of ethyl ether and triturated with methanol to yield 615 mg of 3-[(1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]butanedioicacid, methyl diester (AIT-0075) as an off-white solid. Yield: 31% m.p. 130°-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22]Br)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:21][O:20][C:19]3[CH:24]=[CH:25][C:16]([CH3:15])=[CH:17][CH:18]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: Cc1ccc(OCCBr)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(CCOc3ccc(C)cc3)CC2)cc1
Yield: 82.2 %

Procedure:
From a mixture of 4-(4-methylbenzyl)piperidine (1.14 g, 6.02 mmol), 2-(4-methylphenoxy)ethyl bromide (630 mg, 3.01 mmol) and KI (90 mg) in toluene (20 mL) was obtained 800 mg (85%) of the title compound as a yellow oil, 1H NMR (CDCl3): 1.26-1.38 (m, 2H), 1.45-1.53 (m, 1H), 1.61-1.66 (m, 2H), 1.99-2.07 (m, 2H), 2.277 (s, 3H), 2.317 (s, 3H), 2.494 (d, 2H, J=7), 2.761 (t, 2H, J=6), 2.95-2.99 (m, 2H), 4.067 (t, 2H, J=6), 6.792 (d, 2H, J=78), (d, 2H, J=8), 7.01-7.10 (m, 6H). The hydrocloride, mp 170-1° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](O)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:18])=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:18])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)ncnc2[nH]1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Yield: 100 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.300 g, 1.3 mmol, 1.0 eq.), thionyl chloride (5 ml), and DMF (1 ml). The mixture was refluxed for 4 hour at which time the reaction was poured onto ice and NaHCO3. The aqueous layer was then extracted with ethyl acetate (2×). The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo to give 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a brown solid (0.35 g 100% yield). MS (ESI, negative) for C9H8ClN3O2: 224 (M-H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]=[O:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]Br.C1COCC1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([OH:25])[CH3:26])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carbaldehyde (16.7 mg) which can be prepared according to the method described in Reference example 23, etc. was dissolved in dehydrated THF (0.5 mL; manufactured by Kanto Chemical Co., Inc.). After cooling to 0° C. with the replacement with nitrogen, 0.96 mol/L-methylmagnesium bromide-THF solution (57 μL; manufactured by Kanto Chemical Co., Inc.) and the mixture was stirred overnight while warming to room temperature. To the reaction solution, dehydrated THF (1 mL; manufactured by Kanto Chemical Co., Inc.) and 0.96 mol/L-methylmagnesium bromide-THF solution (1 mL; manufactured by Kanto Chemical Co., Inc.) were added and the mixture was stirred at room temperature for 4.5 hours. To the reaction solution, 2 mol/L hydrochloric acid was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-F”; n-hexane:ethyl acetate 2:1) to obtain the title compound (11.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:6][CH:5]=1.[CH:19](O)=O>C(OC)(OC)OC>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:9][CH:8]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=[CH:19]1
Reactant: COC(=O)c1ccc(Nc2ccccc2N)cc1
Reactant: O=CO
Solvent: COC(OC)OC
Product: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A stirred solution of give 4-(2-aminophenylamino)benzoic acid methyl ester (13 g, 0.054 mol) in trimethyl orthoformate was treated with formic acid (13 mL), heated at reflux temperature for 1 h, cooled to room temperature and concentrated in vacuo. The residual oil was purified by column chromatography (silica, CHCl3/MeOH 1%) to give the title compound in 90% yield, 1H NMR (400 MHz, CDCl3): 8.26-8.28 (m, 3H), 8.17 (s, 1H), 7.90 (bs, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.59 (m, 1H), 7.40 (m, 1H), 7.26 (s, 1H). 3.9 (s, 3H). LCMS (ESI+) 253 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].I[C@@H:8]1[C@H:25]([CH3:26])[C@@:24]2([CH3:27])[C:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])=[CH:10][C:9]1=[O:29]>CN1CCCC1=O>[CH3:26][C:25]1[C@@:24]2([CH3:27])[C:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])=[CH:10][C:9](=[O:29])[CH:8]=1
Reactant: C[C@H]1[C@@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
147.78 mg (2 mmol) of lithium carbonate is heated to 130° C. in 3 ml of N-methyl-pyrrolidone under nitrogen atmosphere. 426 mg (1 mmol) of 2α-iodo-1α-methyl-androst-4-ene-3,17-dione of example 3 is added to this preheated solution. The solution is stirred for another 2 hours at this temperature. After cooling to room temperature, the solution is added in 20 ml of ice water and the product is extracted with ethyl acetate. After evaporation of the solvent, the crude product is purified with ethyl acetate/hexane as mobile solvent by chromatography on silica gel. Concentration by evaporation of the fractions and recrystallization from ethyl acetate yields 178 mg (60% of theory) of 1-methylandrosta-1,4-diene-3,17-dione of melting point 169° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[Br-:10].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[Br:10][C:5]1[C:6]([NH2:9])=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: CSc1ncc(N)cn1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CSc1ncc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
A stirred solution of 2.0 g (14.2 mmol) of 2-methylsulfanylpyrimidin-5-ylamine in 50 mL of dichloromethane and 10 mL of methanol was cooled in an ice bath. 6.08 g (15.6 mmol) of benzyltrimethylammonium tribromide was added in portions over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 3 minutes. The mixture was quenched with saturated aqueous sodium bicarbonate solution until the pH was 8. The organic layer separated and was removed. The aqueous layer was extracted with two 200 mL portions of ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was absorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes to afford 150 mg (5%) 4-bromo-2-methylsulfanylpyrimidin-5-ylamine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1.[I-].[Na+]>ClCCl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:13][CH:12]=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=3)[S:20]([CH3:23])(=[O:21])=[O:22])[CH2:16]2)=[CH:37][CH:36]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(Cn3ccnc3)cc2)C1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
0.055 g of imidazole is added to solution of 0.24 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, in 5 cm3 of dichloromethane. After heating for 3 hours under reflux, the mixture is supplemented with 5 mg of sodium iodide. After stirring for 20 hours under reflux, the reaction mixture is cooled to 20° C. and then chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 20 cm), eluting with 120 cm3 of dichloromethane without fractionating, and then with a dichloromethane and methanol mixture (98/2 and then 96/4 by volume), collecting 4 cm3 fractions. Fractions 12 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.039 g of 1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CC(O)=O.[Br:30]Br>O>[Br:30][C:9]1[S:10][C:6]2[CH2:5][CH2:4][N:3]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:2](=[O:1])[C:7]=2[CH:8]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(Br)cc3C2=O)CC1
Reaction time: 0.17 h

Procedure:
2-4 (0.73 g, 2.0 mmoles) was added to a 50% aqueous HOAc solution (40 ml) and after stirring at 0°-10° for 10 minutes, Br2 (0.32 g, 2.0 mmoles) was added dropwise. After stirring at 0°-10° for 3 hours, the reaction mixture was diluted with 150 ml H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane (85)/acetone (15) to give pure 3-1, Rf 0.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN(OC)[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)(=[O:20])[CH2:18][CH3:19]
Reactant: Oc1ccc(Br)cc1F
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 0.2 h

Procedure:
A mixture of 4-bromo-2-fluorophenol (1.0 g, 5.24 mmol) in tetrahydrofuran (15 mL) was chilled to −78° C. and butyllithium (4.6 mL, 11.5 mmol, 2.5 M solution) was added rapidly, dropwise. The reaction was stirred 12 min and N-methyl-N-methoxypropionamide (the compound of Preparation 9, 0.735 g, 6.28 mmol in 1 mL of tetrahydrofuran with a 1 mL rinse) was added. The reaction was allowed to stir 5 min at −78° C. and then it was warmed to ambient temperature. A few drops of water were added; then the solvent was removed at reduced pressure. The residue was taken up in methylene chloride and washed with aqueous ammonium chloride and brine. The organic layer was dried and concentrated. The residue was flash chromatographed on silica gel (1×2.5 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), discarded forerun; 20% ethyl acetate/hexane (250 mL), 0.186 g of a yellow crystalline solid which had NMR identical to that of preparation 7.