Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3C=C[CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2.P(Cl)(Cl)(Cl)(Cl)Cl.CN(C)C1C=CC=CC=1.[S:44]1C=CC=C1CC(Cl)=O>C1C=CC=CC=1.CO.N1C=CC=CC=1>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:12])[Cl:14])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[S:44][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Reactant: O=C(Cl)Cc1cccs1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cccs3)[C@H]1S2
Temperature: 10 °C
Yield: 8.6 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (1.2 g.) in benzene (30 ml.) were added pyridine (0.36 g.) and phosphorus pentachloride (0.9 g.) under stirring and cooling at 10°C, and the mixture was stirred for 2 hours at room temperature. The solution was cooled at 10°C and absolute methanol (3 ml.) was added to the solution, after which the mixture was stirred for 2 hours at room temperature. Dimethylaniline (2.35 g.) and a solution of (2-thienyl)acetyl chloride (0.42 g.) in anhydrous benzene (5 ml.) were dropwise added to the solution under stirring and cooling at -5°C, and the mixture was stirred for 30 minutes at the same temperature and 1.5 hours at room temperature. The reaction mixture was washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn and then dried. After drying, the solvent was removed and the residue oil was purified by column chromatography on silica gel (20 g.) using chloroform as developing solvent. The eluate was separated into each 50 ml. fraction and the 12th to 14th fractions were concentrated. The residue was crystallized from ether to give crystals of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-[2-(2-thienyl)acetamido]penam-3-carboxylate (105 mg.), mp 144° to 145°C (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH2:26][CH:27]([C:31](OCC)=[O:32])[C:28]([CH3:30])=O)=[O:24].P(Cl)(Cl)(Cl)=O.CCCCCC>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]2[C:7]=1[C:28]([CH3:30])=[C:27]([CH2:26][CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[C:31](=[O:32])[O:8]2
Reactant: CC(CCCc1ccccc1)c1cc(O)cc(O)c1
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCc1c(C)c2c(O)cc(C(C)CCCc3ccccc3)cc2oc1=O
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 2-(3,5-dihydroxyphenyl)-5-phenylpentane (33 g., 0.13 M), (Preparation C) diethyl α-acetoglutarate (32.2 g., 0.14 M) and phosphorous oxychloride (20 g., 0.13 M), protected from atmospheric moisture, is stirred at room temperature. After 10 days, the mixture is dissolved in chloroform, washed three times with water, dried (Na2SO4), and evaporated. The residue is subjected to silica gel chromatography (eluents--9 benzene:1 ether) to yield 22 g. of the desired ester, m.p. 58°-70° C. from hexane. Further recrystallization from ethyl acetate/hexane affords an analytical sample: m.p. 78°-85° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)[C:10]2[CH:21]=[CH:22][C:23]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([C:34]([O:36]CC)=[O:35])[CH2:29]3)(=[O:27])=[O:26])=[CH:24][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO.O.O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][C:16]([F:19])([F:20])[CH2:17][CH2:18]2)[C:10]2[CH:21]=[CH:22][C:23]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([C:34]([OH:36])=[O:35])[CH2:29]3)(=[O:27])=[O:26])=[CH:24][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC[C@H](C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
NaOH (2 mL, 2 M, 4.0 mmol) was added to a solution of ethyl (3S)-1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)piperidine-3-carboxylate (1.4 g, 2.7 mmol) in 80 mL of MeOH—H2O (1:1) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (80 mL). The solvent was concentrated to 80 mL. The resulting solution was neutralized with 2 N HCl. The product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 1.3 g (95%); 1H NMR (400 MHz, CDCl3) δ 1.24-1.27 (m, 1 H), 1527-1.39 (m, 1 H), 1.45-1.59 (m, 2 H), 1.62 (s, 9 H), 1.68 (s, 3 H), 1.70-1.86 (m, 4 H), 1.93-2.06 (m, 1 H), 2.08-2.25 (m, 2 H), 2.33 (t, J=12.11 Hz, 1 H), 2.46 (t, J=10.94 Hz, 1 H), 2.53-2.66 (m, 1 H), 3.69 (d, J=11.72 Hz, 1 H), 3.89 (d, J=9.96 Hz, 1 H), 4.31 (d, J=7.23 Hz, 2 H), 7.48 (d, J=8.79 Hz, 1 H), 7.67 (d, J=8.20 Hz, 1 H), 8.26 (s, 1 H); MS (ESI) (M+H)+=498.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].CCN(CC)CC>C1COCC1.C(Cl)Cl>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1ccc(-n2nnc3c2CCNC3)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ccccn2)C1

Procedure:
A solution of 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (13 mg, 0.065 mmol) in THF (1 mL) was treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (19 mg, 0.078 mmol) followed by Et3N (0.013 mL, 0.097 mmol). After 5 min the reaction was diluted with CH2Cl2 and the organic portion washed with NaHCO3. The organic portion was then dried over Na2SO4, concentrated and purified on 4 g SiO2 to yield 20 mg (75%) of: 5-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C18H13ClF3N5O, 407.1. m/z found, 408.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (dddd, J=32.1, 4.9, 1.8, 0.8 Hz, 1H), 8.17 (ddt, J=17.3, 8.3, 1.0 Hz, 1H), 7.93 (ddt, J=8.4, 7.5, 1.7 Hz, 1H), 7.79 (ddd, J=6.6, 4.4, 2.2 Hz, 1H), 7.57-7.42 (m, 2H), 7.35 (dddd, J=12.3, 7.5, 4.9, 1.0 Hz, 1H), 5.25-4.96 (m, 1H), 4.35 (dt, J=13.3, 5.4 Hz, 1H), 4.11-3.95 (m, 1H), 3.61-3.53 (m, 1H), 3.51-3.44 (m, 1H), 3.36 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:10](=[O:19])[C:9](=[N:20]O)[CH2:8]2.C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1>O>[C:9]([CH2:8][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][C:11]=1[C:10]([OH:19])=[O:29])#[N:20]
Reactant: COCCOc1cc2c(cc1OC)CC(=NO)C2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cc(C(=O)O)c(CC#N)cc1OC
Temperature: 50 °C
Yield: 44.4 %

Procedure:
To a solution of NaOH (5.15 g, 129.2 mmol) in H2O (100 ml) was added 5-Methoxy-6-(2-methoxy-ethoxy)-indan-1,2-dione 2-oxime (9.0 g, 34 mmol), and the mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (8.5 g, 44.2 mmol) was added in portions to the mixture, and the mixture was heated at 80° C. for 15 min. After cooling to room temperature, the precipitate (a little) was filtered. The filtrate was acidified by concentrated HCl to PH=3-4, and the precipitate was collected and dried to give product (4.0 g, 44.1%). LC-MS: m/e 265 (M−1).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:30])=[C:25]([CH2:27][CH2:28]O)[N:26]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(N(CC)CC)C.[CH3:38][NH:39][CH:40]([CH3:42])[CH3:41]>ClCCl.O1CCCC1>[CH:40]([N:39]([CH2:28][CH2:27][C:25]1[N:26]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:15][CH:14]=3)=[CH:21][CH:20]=2)[O:23][C:24]=1[CH3:30])[CH3:38])([CH3:42])[CH3:41]
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCO
Reactant: CNC(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN(C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
Add methanesulfonyl chloride (0.135 g, 0.935 mmol) to a cool (0° C.) solution of 2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethanol (0.257 g, 0.719 mmol) and triethylamine (0.182 g, 1.80 mmol) in dichloromethane (5 mL). Warm to room temperature and stir for 1 hour. Remove the solvents, transfer the residue to a sealed tube, add tetrahydrofuran (5 mL) and N-methyl-isopropylamine (0.526 g, 7.19 mmol), and heat at 60° C. overnight. Add dichloromethane and wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 5% ammoniated methanol in dichloromethane to give isopropyl-{2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-methyl-amine (0.056 g, 18%): mass spectrum (m/e): 413 (M+1). Treat the recovered material (0.056 g, 0.131 mmol) with 1N HCl (144 μL, 0.144 mmol) in ether, concentrate, and lyophilize to give the title compound (12.8 mg): MS (m/e): 413 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12]([O:14][C:15](=[O:16])[C:5]3=[CH:4][CH:3]=1)=O)[CH:8]=[CH:9][CH:10]=2.[CH2:17]([CH:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)CO.CO.O>[CH2:17]([CH:24]([N:32]1[C:12](=[O:14])[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[C:2]([Br:1])=[CH:3][CH:4]=[C:5]3[C:15]1=[O:16])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(N)CCCCCCC
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Solvent: CO
Solvent: O
Solvent: OCCO
Product: CCCCCCCC(CCCCCCC)N1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
5 g (18 mmol) of 4-bromonaphthalene-1,8-dicarboxylic anhydride were heated to 160° C. with 6.1 g (27 mmol) of 1-heptyloctylamine in 50 ml of ethylene glycol for 4 hours. The resulting solution was allowed to cool to room temperature. Thereafter, the solution was diluted with 50 ml of methanol and 50 ml of distilled water. The aqueous solution was extracted with diethyl ether, the solution was dried over MgSO4 and the solvent was evaporated. The resulting yellow oil was purified by column chromatography with dichloromethane as the eluent, which afforded 5.5 g (63%) of the title compound as a colorless oil.
Reaction SMILES: NC(N)=[O:3].[N+]([C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][N:12]1[C:16](=O)[C:15](=[O:18])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=C)([O-])=O.Cl>C(O)(=O)C>[CH2:11]([N:12]1[CH2:16][C:15](=[O:18])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=[O:3])[C:10]1[CH:24]=[CH:25][CH:26]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: C=C1N(CC(=O)O)C(=O)C(=O)N1Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CN(Cc2ccccc2)C1=O
Reaction time: 2 h

Procedure:
A mixture of 1.7 g of the above-prepared urea product of paragraph (1) dissolved in 3 mL of acetic acid and 1 mL of concentrated hydrochloric acid was heated to reflux for four hours. After evaporating the solvent therefrom, 3 mL of acetic acid and 1 mL of concentrated hydrochloric acid were added to the residue followed by stirring for two hours. The resulting component was concentrated, washed well with water and recrystallized from ethanol to give 1.2 g of 1-benzyl-2,4-dioxoimidazolidine-3-acetic acid [Compound 3]. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[S:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[S:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6s5)c(F)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzothiazol-2-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine (0.105 g, 0.283 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.051 g, 41%): 1H NMR (DMSO-d6, 400 MHz) δ 10.51 (s, 1H), 8.80 (m, 1H), 8.24 (s, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.51 (m, 2H), 7.36 (t, 1H), 7.20 (t, 1H), 4.82 (m, 1H), 3.51-2.25 (m, 14H), 2.15-2.10 (m, 2H), 1.80-1.50 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.63 min., 100%; m/z 558 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.[O:11]=[N+:12]=[O:13].F[B-](F)(F)F.CCCCCC>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[C:4]([N+:12]([O-:13])=[O:11])[CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1c([N+](=O)[O-])cc(Cl)c(O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of 6-chloro-2-fluoro-3-methylphenol (9.00 g, 56.1 mmol) in dichloromethane (100 ml) was added dropwise to a suspension of 85% nitronium•tetrafluoroborate (9.50 g, 60.8 mmol) in dichloromethane (150 ml) at 0 to 5° C. under ice-cooling. The resulting mixture was warmed up to room temperature and stirred for 2 hours while maintaining the temperature. The mixture was poured into ice water and then partitioned and extracted with chloroform, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. After the crude product was dissolved in toluene (57 ml) by heating to 80° C., the solution was allowed to cool to 60° C. and maintained at this temperature. Hexane (171 ml) was added dropwise thereto and the resulting mixture was allowed to cool to room temperature and then it was ice-cooled while maintaining temperature. Thereafter, the crystals formed were collected by filtration and dried to obtain 6-chloro-2-fluoro-3-methyl-4-nitrophenol (7.05 g, 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][C:13]1[C:14](=[O:21])[NH:15][N:16]=[C:17]([OH:20])[C:18]=1[Cl:19].C(N(CC)CC)C>CN(C)C=O>[Cl:12][C:13]1[C:14](=[O:21])[NH:15][N:16]=[C:17]([O:20][CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:18]=1[Cl:19]
Reactant: O=c1[nH]nc(O)c(Cl)c1Cl
Reactant: BrCCCSc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(OCCCSc2ccccc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
After 1.57 g of 1-bromo-3-phenylthiopropane, 2 g of 4,5-dichloro-6-hydroxy-3(2H)-pyridazinone and 1.3 g of triethylamine were dissolved in dimethylformamide, the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured onto water. The formed crystals were taken by filtration and thoroughly washed with water. The crystals were recrystallized from ethanol to give 1.5 g of the objective compound. Yield, 52%, Melting point, 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:27](=[S:28])[NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=S)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 4-fluorophenyl isothiocyanate, and diisopropylethyl amine, are reacted to give the product as a white solid. LC-MS: 416 (M++1). 1H NMR (DMSO-d6) δ 3.10 (br.s, 4H), 4.15 (br.s, 4H), 6.20 (s, 1H), 6.45 (br.s, 2H), 7.10 (m, 3H), 7.30 (m, 2H), 7.40 (s, 1H), 7.80 (d, 1H), 9.42 (br.s, 1H).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[OH:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=O)[C@H:18]([OH:29])[CH2:17]4)[CH2:14][CH2:13][C:12]=2[CH:11]=1.[CH3:30][NH2:31].[BH4-].[Na+]>>[CH3:30][NH:31][C@H:19]1[C@H:18]([OH:29])[CH2:17][C@H:16]2[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C:25]1[CH:26]=[CH:27][C:10]([OH:9])=[CH:11][C:12]=1[CH2:13][CH2:14]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Reaction time: 0.08 h

Procedure:
3,16α-Dihydroxy-oestra-1,3,5(10)-trien-17-one diacetate (32.4 g) was stirred with methylamine solution (324 ml; 33% in EtCH) for 20 min. Sodium borohydride (16.2 g) was added portionwise to the stirred solution, keeping the temperature at <25° C. After 11/2 h., the methylamine was removed under reduced pressure and the residue was acidified with hydrochloric acid (5 N). The mixture was rebasified with saturated potassium bicarbonate solution to give crude product, which was filtered off, washed with water and suspended in methanol. The suspension was boiled for 5 min., cooled and filtered to give pure 17β-methylamino-oestra-1,3,5(10)-triene-3,16α-diol as an amorphous solid (23.5 g; 89%), m.p. 242°-246° C. (decomp.), [α]D +48° (c 1.0 in D.M.S.O.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)#[N:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH:13][C:27]([NH:26][C:20]2[N:19]=[C:18]([O:17][CH3:16])[CH:23]=[C:22]([O:24][CH3:25])[N:21]=2)=[O:28])(=[O:12])=[O:11])[CH:9]=1)#[N:2]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COc1ccc(CC#N)cc1S(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(CC#N)ccc2OC)n1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a suspension of 0.3 g of the compound from Example 3 and 0.37 g 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 15 ml of dry acetonitrile was added 0.198 ml DBU. After being stirred overnight the clear solution was diluted with 50 ml of water, acidified with 1N HCl and the precipitate was filtered off. The residue was washed with water and triturated with ether to give 0.44 g solid, m.p. 168°-171° C. (dec.);
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([CH3:16])=[O:15])=[C:10]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([CH3:16])=[O:15])=[C:10]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.870 g (2.60 mmol) of methyl 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonyl-benzoate was dissolved in a mixture of 10 ml of THF and 10 ml of water, and 0.114 g (2.90 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and then evaporated to dryness. The residue was taken up in water, 6 N HCl was added and the mixture was extracted with CH2Cl2. Drying with Na2SO4 and concentration of the organic phase gave 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonylbenzoic acid in the form of a colorless viscous oil.
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[C:10]2[C:17]([C:18]#[C:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[CH:16][N:15]([C@H:30]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[C:11]=2[N:12]=[CH:13][N:14]=1>>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([C:19]#[C:18][C:17]2[C:10]3[C:9]([NH2:8])=[N:14][CH:13]=[N:12][C:11]=3[N:15]([C@H:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)[CH:16]=2)[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 127.5 %

Procedure:
4N-Hydrochloric acid/1,4-dioxane (2 ml) was added to the (S)-tert-butyl 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (30 mg) obtained in Step 3 above, and the mixture was stirred at room temperature for 1.5 hours. After distilling the solvent of the resulting reaction mixture off under reduced pressure, toluene azeotropic distillation was subsequently performed to obtain a crude product of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (30 mg). A portion of the resulting crude product (10 mg), 4-(dimethylamino)but-2-enoic acid hydrochloride (5.9 mg), and HATU (14 mg) were dissolved in DMF (1.0 ml). DIPEA (50 μl) was added thereto and stirred at room temperature for 5 minutes. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (3.9 mg). Table 1 shows the physical properties thereof.