Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(S([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=O)=O)C=CC=1.[CH2:33](OC(=O)C1C=CC(N)=CC=1F)[CH3:34]>>[CH2:33]([O:29][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH:13]=[CH:12][NH:11]3)=[CH:15][CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:34]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CC2
Reactant: CCOC(=O)c1ccc(N)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 475.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reduced to 4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-2-fluoro-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].N=O>>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: N=O
Product: O=CCCCc1ccc(N(CCCl)CCCl)cc1

Procedure:
Similar reaction of 4-[4-(N,N-bis(2-chloroethyl)-amino]phenyl)butanoic acid (VIII, n=3) [Everett, J. L., Roberts, J. J., Ross W. C. J., "Aryl-2-halogenoalkylamines. Part XII. Some carboxylic acid derivatives of N,N-di-2-chloroethylaniline", J. Chem. Soc., 1953 2386-2392] (4.75 g, 15.6 mmol) according to the above protocol gave 4[4-(N,N-bis(2-chloroethyl)amino)phenyl]butanal (IX, n=3) as a pale yellow oil (3.3 g, 73% overall yield). 1H NMR (CDCl3) δ 9.75 (t, J1,2 =1.6 Hz, 1 H, CHO), 7.06 (d, J2',3' =8.6 H z, 2 H, H-2',H-6'), 6.63 (d, J2',3' =8.6 Hz, 2 H, H-3', H-5=), 3.71 (t, J=7.4 Hz, 4 H, NCH2CH2Cl), 3.63 (t, J=7.4 Hz, 4 H, NCH2CH2Cl), 2.56 (t, J3,4 =7.4 Hz, 2 H, H-4), 2.45 (dt, J2,3 =7.3 Hz, and J1,2 =1.6 Hz, 2 H, H-2), 1.90 (quintet, J=7.4 Hz, 2 H, H-3). 13C NMR δ 202.52, 144.41, 130.28, 129.62, 112.21, 53.51, 43.10, 40.59, 33.82, 23.85. HRMS (EI, 70 eV) calcd for C14H19NO35Cl2 : 287.08437. Found: 287.08427.
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C>C1COCC1.O>[C:1]1([C:7]2[CH2:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)Cc2ccccc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To a solution of 2-phenyl-2-hydroxy-2,3-dihydro-1H-indene (6.88 g, 32.76 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature for 3 day. Diethyl ether (200 mL) and water added. Aqueous layer was extracted with diethyl ether (3*200 mL). All etheral layers were combined, washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulphate, and concentrated to yield 5.60 g (92%) of 2-phenyl-1H-indene. 1H-N.M.R. (CDCl3) d 3.78 (t, J=0.8 Hz, 2H), d 7.18-7.48(m, 8H), d 7.63(br d, J=7.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:20])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:30])[NH2:20]
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC(=S)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (1.8 g, 6.0 mmol), Lawesson's reagent (4.85 g, 12.0 mmol), toluene (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with 20-50% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbothioic acid amide (1.4 g, 4.5 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](C2C=CC(F)=CC=2)=[N:8][NH:7][N:6]=1)=[O:4].[H-].[Na+].O.[CH2:20]1COCC1>>[CH3:1][O:2][C:3]([C:5]1[NH:6][NH:7][N:8]([CH3:20])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1n[nH]nc1-c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=CN(C)NN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
5-(4-Fluoro-phenyl)-2H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.21 g, 10 mmol) in THF (10 ml) was added drop-wise to an ice-cooled slurry of sodium hydride (0.42 g, 60% dispersion in mineral oil, 10 mmol) in TEF (45 ml), under argon. After stirring at room temperature for 1 h, the reaction mixture was heated at 80° C. for 16 h. Water was added to the cooled mixture and the product was extracted with diethyl ether (2×). The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 10-50% ethyl acetate-pentane) afforded 5-4-Fluoro-phenyl)-1-methyl-2H-[1,2,3]triazole4-carboxylic acid methyl ester (763 mg, 33%) and the title compound (943 mg, 40%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([NH2:11])[C@H:6]1[O:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[CH2:5]([N:11]=[C:1]=[O:2])[C@H:6]1[O:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: NC[C@@H]1CCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=NC[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of phosgene (2 mL of a ˜20% in toluene, 4.44 mmol) in 5 mL of dichloromethane at 0° C. was added a solution of (S)-tetrahydrofurfurylamine (0.15 mL, 1.48 mmol) and triethylamine (0.45 mL, 3.26 mmol) in 4 mL of dichloromethane dropwise over 20 min. The reaction mixture was stirred for 2.5 h at room temperature. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ether. The triethylamine hydrochloride salt was removed by filtration. Concentration afforded 46A as a clear oil in quantitative yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1B1OC(C)(C)C(C)(C)O1)([CH3:13])([CH3:12])[CH3:11]>CO.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)(C)NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Temperature: 25 °C

Procedure:
A solution of 37.0 g (129 mmol) of Na2CO3(H2O)10 in a mixture of 200 ml of methanol and 600 ml of water was added to a mixture of 9.58 g (51.5 mmol) of 6-bromopyridine-2-carbaldehyde, 17.5 g (51.5 mmol) of tert-butyl{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}amine and 3.00 g (2.60 mmol) of Pd(PPh3)4 in 1000 ml of toluene by vigorous stirring at room temperature. The resulting mixture was stirred at 80° C. for 12 h. Further on, this mixture was cooled to room temperature; the organic layer was separated and evaporated to dryness. The residue was dissolved in 700 ml of 2 M HCl, and this solution was extracted with 3×200 ml of toluene. To the aqueous layer a solution of K2CO3 was added to pH 9, and the product was extracted with 2×300 ml of dichloromethane. This organic extract was dried over MgSO4 and then evaporated to dryness. Yield 15.2 g (46%). Anal. calc. for C21H22N2O: C, 79.21; H, 6.96; N, 8.80. Found: C, 79.30; H, 7.14; N, 8.65. 1H NMR (CDCl3): 10.18 (s, 1H, CHO), 8.07 (m, 1H, 3-H in Py), 8.02 (m, 1H, 4-H in Py), 7.92 (m, 1H, 8-H in naphthyl), 7.88 (m, 1H, 5-H in naphthyl), 7.71 (m, 1H, 5-H in Py), 7.66 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.36 (m, 1H, 6-H in naphthyl), 7.28 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 3.53 (m, 2H, CH2N), 1.55 (br. s, 1H, NH), 0.94 (s, 9H, tBu).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>CC(C)=O>[C:20]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)#[C:21][CH3:22]
Reactant: C#CCBr
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(C)cc(=O)oc2c1

Procedure:
A mixture of 7-hydroxy-4-methylcoumarin (1.76 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 1.93 g of a product with the following characteristics: m.p.140-141° C.; 1H NMR (CDCl3) δ: 2.4 (s), 2.69 (m), 4.8 (s, 2H), 6.15-7.58 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][C:13](=O)[NH:14][C:9]=3[CH:8]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:2]=1
Reactant: O=C1COc2ncc(-c3cccnc3)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cncc(-c2cnc3c(c2)NCCO3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
7-pyridin-3-yl-1H-pyrido[2,3-b][1,4]oxazin-2-one (60 mg, 0.264 mmol) was dissolved in 4 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and the mixture was cooled to 0□, and 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (0.7 ml, 0.704 mmol) was added thereto dropwise at room temperature for 5 hours. To the reaction mixture, water (0.3 ml), 10% sodium hydroxide (0.6 ml) and water (0.9 ml) were added dropwise in this order, and then stirred vigorously at room temperature for 1 hour. The formed solid was filtered and washed with excess ethyl acetate. The filtrate was washed with water and saturated saline solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to obtain 7-pyridin-3-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (30 mg, 53%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH:19]3[CH2:28][CH2:27][C:22]4(OCC[O:23]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][C:4]=1[F:29].CO>CC(C)=O.C(Cl)Cl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([NH2:2])=[C:4]([F:29])[CH:5]=3)=[CH:10][N:11]([CH:19]3[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Nc1ccc(-c2cn(C3CCC4(CC3)OCCO4)c3ncnc(N)c23)cc1F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: Nc1ccc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Yield: 77328568 %

Procedure:
5M HCl (300 mL) was added slowly to a solution of 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (18.49 g, 48.28 nmol) in acetone (800 mL) at 0° C. the resulting dark orange-brown solution was heated at 60° C. for 4 h. (t.l.c. analysis using 10% MeOH in CH2Cl2). The acetone was removed under reduced pressure and the acidic layer was basified to approx. pH 8 using sat. aq. Na2CO3. The resulting precipitate was collect by filtration and scrupulously dried to afford 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a light brown solid (12.67 g, 77%). A second crop was also obtained from the mother liquor on standing (2.01 g, 12%), 1H NMR (400 MHz, d6-DMSO) 2.27(2H, m), 2.30 (4H, br d), 2.73(2H, m), 5.14(1H, m), 5.20(2H, brs), 6.05(2H, brs), 6.85 (1H, t), 6.97(1H, dd), 7.06(1H, dd), 7.35(1H, s) and 8.12(1H, s) and m/z 340.1(MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH2:16][C:15]([F:20])([C:17]([OH:19])=O)[CH:14]=[CH:13][C:12]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.C(OCC)(=O)C.O>[O:52]=[C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:57][CH2:58]1)[CH2:50][NH:49][C:17]([C:15]1([F:20])[CH:14]=[CH:13][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([F:10])[CH2:16]1)=[O:19]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)C1(F)C=CC(c2ccccc2)=C(F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)C1(F)C=CC(c2ccccc2)=C(F)C1)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
DIPEA (83 mg, 0.11 mL, 0.21 mmol) was added to a stirred solution of 2,4-difluoro-biphenyl-4-carboxylic acid (50 mg, 0.21 mmol) in DMF (1 mL). HOBT (35 mg, 0.25 mmol) and EDCI (50 mg, 0.25 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (90 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and then extrated with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford 56.9 mg (50.35%) of 2,4-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.42%. 1H NMR (DMSO-d6): δ 8.2-7.94 (d, 2H), 7.88-7.74 (m, 2H), 7.74-7.6 (m, 4H), 7.6-7.5 (m, 1H), 7.46-7.34 (m, 1H), 7.3-7.2 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.4 (m, 6H), 3.2-3.0 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+]>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-3-nitropyridine (4.0 grams) and 4-chlorothiophenol (3.7 grams) were mixed in 100 ml. of dry DMF and lithium hydroxide (1.2 grams) added portionwise. After the reaction mixture had stirred for about 5 minutes, it darkened and became warm. It was allowed to stir with a drying tube for 4 hours, poured over ice water and the product separated by filtration. It was crystallized from ethyl acetate-ethanol, yield: 5.0 grams, m.p. 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:41]([O:45][C:46](=[O:52])[NH:47][CH2:48][CH2:49][CH2:50]Br)([CH3:44])([CH3:43])[CH3:42]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:50][CH2:49][CH2:48][NH:47][C:46]([O:45][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:52])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1cc(C)c(-c2cc(Sc3cccc(O)c3)nc(N)n2)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C)c(-c2cc(Sc3cccc(OCCCNC(=O)OC(C)(C)C)c3)nc(N)n2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
5-[2-Amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-ethoxy-4-methylbenzoic acid methyl ester (110 mg, 0.27 mmol) obtained in Step 1 above, cesium carbonate (133 mg, 0.41 mmol), and N,N-dimethylformamide (1.2 ml) were added to a reaction vessel, and then 3-bromopropylcarbamic acid tert-butyl ester (97 mg, 0.41 mmol) was added thereto. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous ammonium chloride solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:3) to yield 5-{2-amino-6-[3-(3-tert-butoxycarbonylaminopropoxy)phenylsulfanyl]pyrimidin-4-yl}-2-ethoxy-4-methylbenzoic acid methyl ester (145 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=[C:5]2[CH2:4]1)[CH3:2].[Li][CH2:18]CCC.CI>CC#N>[CH2:15]([C:3]1([CH2:1][CH3:2])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][C:9]([CH3:18])=[C:5]2[CH2:4]1)[CH3:16]
Reactant: CCC1(CC)CCc2c(csc2C(=O)O)C1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CC#N
Product: CCC1(CC)CCc2c(C(=O)O)sc(C)c2C1

Procedure:
5,5-Diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid is prepared from 5,5-diethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid by treatment with tert.-BuLi followed by methyliodide in analogy to Example C; LC-MS: tR=1.03 min, [M+1+CH3CN]=294.27.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11](O)[C:10]=2[CH:21]=1>C1C=CC=CC=1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([Cl:3])[C:10]=2[CH:21]=1
Reactant: OC1c2ccccc2C=Cc2ccc(Br)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1c2ccccc2C=Cc2ccc(Br)cc21
Yield: 92.5 %

Procedure:
12.8 grams (0.11 mole) of thionyl chloride was added to a solution of 24.6 grams (0.086 mole) of 3-bromo-5H-dibenzo[a,d]cyclohepten-5-ol in 750 milliliters of benzene and the resulting mixture heated at reflux temperature for two hours. At the end of this period, the mixture was cooled, concentrated to dryness in vacuo to obtain 24.3 grams of 3-bromo-5-chloro-5H-dibenzo[a,d]cycloheptene intermediate compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][O:5][CH2:6][C:7](O)=[O:8].C1(N=C=NC2CCCCC2)CCCCC1>CO>[O:8]=[C:7]1[CH2:6][O:5][CH2:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[NH:1]1
Reactant: Nc1ccccc1COCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: O=C1COCc2ccccc2N1

Procedure:
1 g o-amino-benzyloxy acetic acid and 1.1 g dicyclohexyl carbodiimide were stirred in 15 ml refluxing methanol for 8 hours. The mixture was evaporated, and the residue was stirred with 50 ml acetone and filtered, whereafter the filtrate was evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[C:22]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:23]=2[N:24]=[CH:25][N:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:21]2[C:22]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ncnc2c(-c3ccc(S(C)(=O)=O)cc3)noc12
Reaction time: 0.17 h
Yield: 324.6 %

Procedure:
4-Ethylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient temperature. After stirring for 10 min, 7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine (0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and concentrated under vacuum. The residue was subjected to SiO2 with ethyl acetate and hexane (1/1) to afford Compound D2 (0.82 g, 61%). 1H NMR (400 Mz, DMSO-d6) δ 8.49 (s, 1H), 8.41 (d, J=7.1, 2H), 8.34 (d, J=7.1, 2H), 4.10˜3.74 (m, 7H), 3.52 (m, 1H), 3.25 (t, 3H), 1.41˜1.22 (m, 4H). LCMS 516.3 [M+H].
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11](Cl)([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>O1CCOCC1.C(Cl)Cl.CO>[C:11]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1([NH2:1])[C:8]([OH:10])=[O:9])([O:13][CH2:14][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(C(=O)O)CCCCC1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
The title compound is prepared from 1-aminocyclohexane carboxylic acid (700 mmol), FMOC-chloride (770 mmol), Diisopropyl-ethylamine (770 mmol) and 770 ml NaOH 1N in 950 ml dioxan by conventional methods. Mp. 180-182° C.; Rf=0.21 (CH2Cl2/MeOH=95:5)
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH3:46])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C=O)C>[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:11])[CH3:12])[NH:9][C:33](=[O:32])[C@H:34]([CH3:46])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of L-valine tert-butyl ester hydrochloride (2.1 g, 10 mmole) in DMF (10 ml) was treated with DIEA (1.6 ml. 10 mmole) and benzyloxycarbonyl-L-alanine p-nitrophenyl ester (3.5 g, 10 mmole). After overnight at room temperature, the solution was filtered through a column of neutral Al2O3 (100 g) and eluted with DMF. The solvent was removed in vacuo and the residue filtered through a column of silica gel (50 g) eluted with CHCl3. The resulting oil (3.0 g, 79%) was homogeneous on tlc; Rf (CHCl3) 0.10; Rf (ether) 0.70; Rf (CHCl3 24, CH3OH 1) 0.55.