Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:27]([NH:26][CH2:3][C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:5]=2)=[O:28])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Reactant: [N-]=C=O
Agent: Cl
Product: O=C(NCc1ccccc1)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzydryloxy]azetidine hydrochloride (125) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:7][C:6]1=[O:26])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>C(OCC)(=O)C.O>[C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[C:6]1=[O:26])(=[O:3])[CH3:2]
Reactant: COc1ccc([C@@H]2SC=C(c3ccccc3)NC(=O)[C@H]2OC(C)=O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A mixture of 1.1 g (0.003 mol) of rac.-trans-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl) -3-phenyl-1,4-thiazepin-5(4H)-one, 0.5 g of potassium carbonate (powdered) and 0.3 g (0.003 mol) of 2-dimethylaminoethyl chloride in 25 mL of ethyl acetate was stirred and heated at reflux for 2 hrs, then twice an additional 0.15 g of 2-dimethylaminoethyl chloride was added at 2 hr intervals. The mixture was heated at reflux for a total of 12 hrs., cooled to room temperature and diluted with water. The aqueous suspension was extracted with ethyl acetate then the organic solution was washed with brine and dried (MgSO4). Removal of the solvent gave 1.2 g (92%) of rac.-trans-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl) -4-[2-(dimethylamino)ethyl]-3-phenyl-1,4-thiazepin-5(4H) -one. Analytical sample was recrystallized from ether, mp 147°-148°.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1.C(#N)C.C(N(CC)CC)C.[Cl:31][C:32]1[S:36][C:35]([CH:37]=[CH:38][S:39](Cl)(=[O:41])=[O:40])=[CH:34][CH:33]=1>C(OCC)(=O)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([S:39]([CH:38]=[CH:37][C:35]4[S:36][C:32]([Cl:31])=[CH:33][CH:34]=4)(=[O:41])=[O:40])[CH2:16][C:15]3=[O:20])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: O=C1CNCCN1Cc1ccc2c(Cl)cnnc2c1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1ccc2c(Cl)cnnc2c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
1-(4-chlorocinnolin-7-ylmethyl)-piperazin-2-one hydrochloride (0.14 g, 0.4 mmol), EXAMPLE 90, is treated with acetonitrile (20 mL), triethylamine (2 mL, 14 mmol) and 2-(5-chlorothiophen-2-yl)ethene-sulfonyl chloride (0.097 g, 0.4 mmol), EXAMPLE 3, at 0° C. The solution is warmed to ambient temperature over 1.5 h and diluted with ethyl acetate. The solution is washed with 10% sodium bicarbonate solution and water, dried (sodium sulfate) and concentrated to yield the title compound (0.17 g, 0.35 mmol). MS m/z: [M+H]+=483; 1H NMR (CDCl3, 300 MHz) δ9.4 (s, 1H), 8.4 (s, 1H), 8.3 (d, 1H) 7.85 (d, 1H), 7.7 (d, 1H), 7.1 (d, 1H), 6.95 (d, 1H), 6.35 (d, 1H), 4.9 (s, 2H), 4.0 (s, 2H), 3.4-3.5 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].Cl[CH:21](Cl)[CH2:22][Si:23]([Cl:26])([Cl:25])[Cl:24]>C(=S)=S.CCCCCC>[Cl:24][Si:23]([CH2:22][CH:21]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:26])[Cl:25]
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Reactant: c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Agent: [Al]
Solvent: S=C=S
Solvent: CCCCCC
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccc(-c3ccccc3)cc21
Yield: 10 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of para-terphenyl and 0.30 g (11.1 mmol) of aluminum were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)trichlorosilane 6.68 g (21.7 mmol) under dry nitrogen atmospheric pressure for 24 hrs at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, recrystallization from ether yielded 0.85 g of 9-(trichlorosilyl)methyl-2-phenylfluorene (yield; 10%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([Cl:16])[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O1CCOCC1.Cl>O>[ClH:16].[CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)c([N+](=O)[O-])c21
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(N(C)C)c3c2[N+](=O)[O-])CC1
Yield: 83.7 %

Procedure:
A mixture of 3.3 g of 1-dimethylamino-7-chloro-6-fluoro-8-nitro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.1 g of 1-methylpiperazine and 25 ml of dioxane is refluxed for 3 hours. The solvent is stripped off in vacuo, the residue is suspended in 25 ml of H2O and the pH is brought to 1 with 10% strength hydrochloric acid. The precipitate is filtered off with suction in the cold and washed with a little cold 10% strength hydrochloric acid and ethanol. 3.6 g of 1-dimethylamino-6-fluoro-8-nitro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochoride of decomposition point 292°-294° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][CH:15]([F:18])[CH2:16][OH:17].CC([O-])(C)C.[K+].C(Cl)Cl.CCO>C1COCC1>[F:14][CH:15]([F:18])[CH2:16][O:17][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OCC(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
Prepared analogously to Example 5a from 2 chloro-5-nitro nicotinic acid and 2,2-difluoroethanol with KOtBu in THF. Yield: (25%). MS [M−H]−=247; TLC: Rf=0.13 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[S:29]/4)=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH3:43]N(C)C=O.[H-].[Na+].CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[N:27]([CH3:43])[C:28](=[O:30])[S:29]/4)=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)N(C)C2=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a mixture of (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-1,3-thiazolidine-2,4-dione (0.50 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, methyl iodide (0.16 g) was added, and the mixture was further stirred at room temperature for 30 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (0.47 g, yield 92%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 215-216° C.
Reaction SMILES: [H-].[Na+].CS([O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.S([O-])(=O)(=O)C.C1(C)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:40]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:35]=1O>CN(C)C=O>[CH3:32][O:33][C:34]1[C:35]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9]2)=[C:36]2[C:40](=[CH:41][CH:42]=1)[CH2:39][CH2:38][CH2:37]2
Reactant: COc1ccc2c(c1O)CCC2
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1O[C@H]1CCN(Cc3ccccc3)C1)CCC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In 540 ml of anhydrous dimethylformamide 5 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol were dissolved. The solution was stirred, placed under a steam of nitrogen and 1.5 g of a 60% dispersion of sodium hydride in oil was added. The reaction mixture was stirred at room temperature for half an hour. The temperature was raised to 100° C. and a solution of 7.78 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine in 78 ml of anhydrous dimethylformamide was added dropwise over 1 hour. Another 3,0 g of mesylate in 30 ml of anhydrous dimethylformamide were added dropwise over 0.5 hours and the reaction continued for another 1.5 hours at 100° C. Evaporation in vacuo gave a semi solid that was partitioned between water and ethyl acetate. The ethyl acetate extract was dried and evaporated in vacuo. The derived product was isolated by chromatography over silica using toluene/-ethanol as the eluent giving 9.45g of (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine as an oil. M.S. (C.I.) (M/Z): 324 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][CH2:36][C:37]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[CH:17][S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1-B; 67 mg, 0.258 mmol) in 1 mL CH2Cl2 at room temperature under nitrogen was added diisopropylethylamine (68 μL, 0.387 mmol) followed by 2-(benzyloxy)acetyl chloride (41 μL, 0.258 mmol). After 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a yellow oil (68 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.51 (d, 1H), 8.44 (br s, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 7.39 (m, 5H), 7.24 (m, 3H), 6.50 (d, 1H), 4.68 (s, 2H), 4.13 (s, 2H). LRMS (ESI pos) m/e 409.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.C([Li])(C)(C)C.CO[NH2:28].O>CCCCCC.CCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:28])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1
Reactant: CON
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCCC
Solvent: CCCCC
Product: CN1CCC2(CC1)c1ccccc1Oc1c(N)cccc12
Temperature: 25 °C

Procedure:
To a solution of 1'-methylxanthene-9-spiro-4'-piperidine (1.3 g.) in hexane (25 ml.) in an argon atmosphere is added a 1.6 molar solution of t-butyl lithium in pentane (3.5 ml.) with stirring at room temperature. The mixture is stirred for 1 hour at room temperature. Hydroxylamine methyl ether (0.4 g.) in hexane (5 ml.) is added dropwise during 5 minutes. Water is added and the organic layer separated, washed with water and dried with MgSO4. The solvent is evaporated to give a solid residue, which is recrystallised from hexane to give 1'-methyl-4-aminoxanthene-9-spiro-4'-piperidine, m.p. 173°-174° C. The above process is repeated using an equivalent amount of sulphur and paraformaldehyde as starting material in place of hydroxylamine methyl ether. The following compounds are thus prepared:
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5](Cl)=[O:6].[NH2:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][C:17]([CH:38]=[CH:39][O:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42])=[C:18]2[C:22]([O:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:25]([O:24][C:22]([C:18]1[N:19]2[CH:14]([S:15][CH2:16][C:17]=1[CH:38]=[CH:39][O:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42])[CH:13]([NH:12][C:5](=[O:6])[C:4](=[N:8][O:9][CH3:10])[C:3](=[O:11])[CH2:2][Br:1])[C:20]2=[O:21])=[O:23])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CON=C(C(=O)Cl)C(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride syn isomer (2 g) in acetone (10 cc) is added, in the course of 7 minutes, to a solution, cooled to -10° C., of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene, E-form (4.7 g) in acetone (50 cc), water (5 cc) and sodium bicarbonate (2.8 g). The mixture is stirred for 1 hour at -10° C. and is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). Crude 2-benzhydryloxycarbonyl-7-(4-bromo-2-methoxyimino-3-oxo-butyrylamino)-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (11 g) is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, grey solid (45 mg, 51%), MS (ISP) m/z=352.6 [(M+H)+], mp 265° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.ClCCl>[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14]([Cl:4])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
52.08 g (0.33 mol) oxalyl chloride is slowly added dropwise at 20° C. to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 mL of dichloromethane, and 4 drops of dimethylformamide. It is stirred for 1 hour at 20° C. and 0.5 hour at 50° C. The solvent is distilled off and the residue remaining is used in the next step without any further purification.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C[Al](C)C>C1COCC1>[OH:42][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@:3]3([C:11]4[CH2:12][C:13]5[C:18]([CH:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[OH:1])=[CH:31][CH:30]=2)=[CH:41][C:37]=1[C:38]([OH:40])=[O:39]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Yield: 30.2 %

Procedure:
To a mixture of ethyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (11, 200 mg, 0.48 mmol), 5-amino-2-hydroxybenzoic acid (75 mg, 0.48 mmol) and THF (1.0 mL) in a 5 mL microwave vial, was added trimethylaluminium (0.5 mL, 20% solution in toluene) and the mixture irradiated at 100° C. for 5 min. The reaction mixture was quenched with slow addition of 1.5 N HCl (2 mL) and extracted with ethyl acetate (3×15 mL). Organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue purified by preparative HPLC [Kromasil C18 (250×50 mm), flow rate: 40 mL/min, 0.1% TFA in water/MeOH, run time: 40 min] to yield 75 mg (30%) of the title compound as an off white solid.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1>COCCO>[CH2:1]([NH:4][C:5]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN=C=O
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: COCCO
Product: CCCNC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
Propyl isocyanate (2.38 g) was added dropwise to 5.13 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of 2-methoxyethanol. The mixture was stirred at room temperature for 10 minutes. Crystals precipitated were collected by filtration and recrystallized from methanol-acetonitrile to obtain 4.91 g of 2(propylcarbamoyl) amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CCO)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(CCO)CC2CNCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (Compound 67-D) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hour and then the solvent was removed in vacuum to give the crude product 70-A, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[CH:4][S:5][C:6]=1[CH2:7][CH3:8].[ClH:12].[CH:13](O)([CH3:15])[CH3:14]>>[ClH:12].[CH:13]([O:10][C:9]([C:3]1[C:2]([NH2:1])=[C:6]([CH2:7][CH3:8])[S:5][CH:4]=1)=[O:11])([CH3:15])[CH3:14]
Reactant: CCc1scc(C(=O)O)c1N
Reactant: CC(C)O
Agent: Cl
Product: CCc1scc(C(=O)OC(C)C)c1N

Procedure:
A sample of 1.02 g. (4.610 mmols) of 4-amino-5-ethyl-3-thiophenecarboxylic acid was dissolved in 50 ml. of isopropanol which had been previously saturated with gaseous hydrogen chloride. The resulting reaction was heated under reflux for 48 hours, cooled and evaporated to afford 0.927 g. (81%) of pure 4-amino-5-ethyl-3-thiophenecarboxylic acid isopropyl ester hydrochloride, m.p. 159° C. (dec.) after recrystallization from isopropanol/ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].N1C=CC=CC=1.[C:16](Cl)(=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:16](=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCNCCOC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCN(CCOC)C(=O)OC(C)Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled solution of bis(2-methoxyethyl)amine (1.94 g, 14.5 mmol, Aldrich) and pyridine (1.26 g, 1.29 mL, 15.9 mmol) in methylene chloride (18 mL) at −78° C., was added slowly 1-chloroethyl carbonochloridate (1.98 g, 1.5 mL, 13.8 mmol, Aldrich) over ˜15 min. The reaction mixture was allowed to stir at −78° C. for 3 h, giving a white precipitate. This cold reaction mixture was filtered to remove the solid and the filtrate was concentrated to dryness, giving the crude 1-chloroethyl bis(2-methoxyethyl)carbamate used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C(N(CC)CC)C.Cl>ClCCl.C(OCC)(=O)C>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])=[O:13]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloroaniline (5.15 g, 40.37 mmol) in dichloromethane (50 mL) was added 2,4-dichlorobenzoyl chloride 1 (8.88 g, 42.39 mmol) and then triethylamine (6.1 mL, 44 mmol). The reaction mixture was stirred overnight at ambient temperature and ethyl acetate (150 mL) was added followed by 1N HCl (50 mL). The organic phase was washed with water and brine, dried, and concentrated under reduced pressure to yield a light yellow solid. 2,4-dichloro-N-(2-chlorophenyl)benzamide 2 was used for the next step without further purification. Yield: 11 g, 90%.