Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:26][CH2:27]Br.O>CN(C)C=O>[CH:6]1[C:7]2[C:8]3[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][C:13]=3[O:14][CH2:27][CH2:26][O:1][C:2]=2[CH:3]=[CH:4][C:5]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(O)c(-c2cc(C#N)ccc2O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)-c1cc(C#N)ccc1OCCO2
Temperature: 150 °C
Yield: 29.8 %

Procedure:
A mixture of 6,6'-dihydroxy[1,1'biphenyl]-3,3'-dicarbonitrile (11.8 g), sodium carbonate (10.6 g), and 1,2-dibromoethane (8.4 g) in 250 ml of anhydrous dimethylformamide is heated at 150° C for 18 hours under nitrogen. The reaction mixture is poured into water and extracted with three 200 ml portions of dichloromethane. The dichloromethane extracts are combined and washed with 10% sodium hydroxide, water, and brine. The solution is filtered through 100 ml of silica gel and concentrated. The resultant solid is recrystallized from benzene to yield 3.5 g of the title compound, melting point 195-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([S:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[F-].[Cs+]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:25][CH2:24][C:23]([O:27][CH3:28])=[O:26])[C:12]([S:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)c1nc(SC)n(CCC(=O)OC)c(=O)c1OCc1ccccc1
Yield: 82 %

Procedure:
Reaction of intermediate 1, ethyl 5-benzyloxy-2-methylthio-6-oxo-1,6-dihydro-pyrimidine-4-carboxylate, (1.500 g, 4.68 mmol) with methyl acrylate (25 ml) and cesium fluoride (0.19 g) for 18 h as described for the preparation of intermediate 6 gave 1.560 g (82% yield) of the title ester as a white solid; mp 62–63° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.1 Hz, CH3), 2.59 (3H, s, SCH3), 2.78 (2H, m, CH2), 3.72 (3H, s, OCH3), 4.34 (4H, m, OCH2 and NCH2), 5.19 (2H, s, OCH2), 7.34 (3H, m, aromatics), 7.46 (2H, m, aromatics). MS (ESI+) m/z 407 [M+H+].
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1>C(OCC)C.CS(C)=O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1([CH2:14][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH2:4][O:16]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Sodium hydride (3.78 g, 0.079 mole as 50% dispersion in oil) was suspended, with stirring, in 20 ml of dry diethyl ether. The ether was then removed by decantation, and the sodium hydride was dried in a stream of dry nitrogen. 100 Ml of dry dimethyl sulphoxide was added followed by 17.34 g (0.079 mole) of dry powdered trimethylsulphoxonium iodide, in portions, over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20° C.). 2-(1H-1,2,4-Triazol-1-yl)-2',4'-dichloroacetophenone (18.33 g, 0.072 mole) as a solution in 50 ml of dry dimethyl sulphoxide was then added. The mixture was heated at 60° C. for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was cooled and quenched in ice and the product was then extracted into ethyl acetate (600 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, and concentrated to give a red gum. Column chromatography of the gum on silica, eluting with ether, gave 6.62 g (34.4%) of the title compound as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[Cl:14][C:15]1[S:19][C:18]([NH:20][S:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([C:33]#[N:34])[CH:25]=2)(=[O:23])=[O:22])=[N:17][CH:16]=1>>[Cl:14][C:15]1[S:19][C:18]([NH:20][S:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:2]([F:1])[CH:3]=3)=[O:29])=[C:26]([C:33]#[N:34])[CH:25]=2)(=[O:23])=[O:22])=[N:17][CH:16]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)NCc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-fluoro-4-(trifluoromethyl)benzylamine and 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}-2-cyanobenzoic acid of Preparation 22, following Method O described for Example 344. The reaction mixture was stirred at room temperature for 18 hours.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[ClH:50]>CO.[H][H]>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[ClH:50]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@H](N)CCCC(=O)OC(C)(C)C)C(C)C

Procedure:
Pd-on-charcoal catalyst is added to a solution of 2.3 g of Z-D-Aad(OBut)-Val-Tyr(But)-OMe in 100 ml of methanol and hydrogen is passed through the solution at pH 4.5 (autotitrator), while stirring and while adding approx. 2 N methanolic hydrochloric acid, until no further methanolic hydrochloric acid is taken up. The catalyst is then filtered off and the filtrate is concentrated. Yield 1.98 g, melting point 85°-87°, [α]D22 =-14.9° (c=1, methanol).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)(O)=[O:2].C(Cl)(Cl)[Cl:21].S(Cl)(Cl)=O>CN(C)C=O>[Cl:21][C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)=[O:2]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
A solution of 2.50 g. of 2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene in 50 ml. of chloroform, 10 ml. of thionyl chloride and 0.3 ml. of dimethylformamide is stirred for 8 hours, then evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in 50 ml. of chloroform and added to a 3-fold excess of ethereal diazomethane at 0° C. After 12 hours the solution is evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene. A solution of 1.37 g. of the latter compound in 50 ml. of tetrahydrofuran is added to 10 ml. of 0.1 N sulfuric acid containing 0.5 g. of copper powder. The mixture is refluxed for 3 hours and then cooled, filtered and poured into water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene which is recrystallized from chloroform/hexane. A solution of 0.05 g. of cupric acetate monohydrate in 5 ml. of acetic acid is heated to 100° C. and 3.0 g. of granular zinc is added. The mixture is shaken for 3 minutes and the acetic acid is then decanted. The residual zinc-copper couple is washed three times with 5 ml. portions of acetic acid, then three times with 5 ml. portions of ether. It is then refluxed for 4 hours under nitrogen in 20 ml. of ether containing 2.5 ml. of methylene iodide, 1.32 g. of 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene is added, and reflux is continued for a further 4 hours. The mixture is cooled and diluted with 50 ml. of benzene. The liquid phase is decanted and washed with water and aqueous sodium bisulfate, then dried and evaporated. The residue is chromatographed on 50 gm. of silica gel, eluting with ethyl acetate/hexane, to yield 2-(5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)prop-1-en-3-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccnc(Nc2ccccc2)n1
Temperature: 100 °C
Yield: 11.8 %

Procedure:
In a sealed tube was 2-chloro-4-methoxypyrimidine (1.00 g, 6.92 mmol) in 2-propanol (5 mL). Aniline (0.757 mL, 8.30 mmol) and DIEA (1.45 mL, 8.30 mmol) were added and the reaction mixture was stirred at 100° C. until the reaction was complete by HPLC. The reaction mixture was cooled to room temperature. The resulting thick suspension was filtered, washed with ethanol, collected and dried under vacuum to yield the desired product (0.164 g) as a white solid. The filtrate was concentrated and then partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a yellow solid. The crude product was purified by flash column chromatography, eluting with 25:1 dichloromethane/EtOAc. The desired product (0.548 g) was obtained as a white solid, which was combined with the filtered product to yield 0.712 g (51%) total desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.20 (d, J=5.5 Hz, 1H), 7.77 (d, J=7.8 Hz, 2H), 7.27 (t, J=8.0 Hz, 2H), 6.94 (t, J=7.4 Hz, 1H), 6.28 (d, J=5.5 Hz, 1H), 3.91 (s, 3H). LRMS (ESI pos) m/e 202 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:12])=[N:6][C:7]([Cl:11])=[N:8][C:9]=1Cl)([OH:3])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][NH2:18].C(N(CC)CC)C>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][NH:18][C:9]1[C:4]([C:1]([OH:3])=[O:2])=[C:5]([Cl:12])[N:6]=[C:7]([Cl:11])[N:8]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(Cl)nc(Cl)c2C(=O)O)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 5-carboxy-2,4,6-trichloropyrimidine 10.0 g in dimethylformamide 45 ml is added a suspension of 3-chloro-4-methoxybenzylamine 4.82 g and triethylamine 6.98 ml in dimethylformamide 40 ml over a period of 20 minutes on ice bath, and the mixture is stirred for 1 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2,6-dichloropyrimidine as a pale brown solid, 17.59 g. mp 150-151° C.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[C:9]([CH:15]=O)[CH:8]=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:17][O:18][NH2:19].Cl>CCO.N1C=CC=CC=1>[CH3:17][O:18][N:19]=[CH:15][C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]3[C:14]=2[C:10]=1[CH:11]=[CH:12]3
Reactant: CON
Reactant: O=Cc1ccc2c3c1ccn3C(=O)CNC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=Cc1ccc2c3c1ccn3C(=O)CNC2
Yield: 23 %

Procedure:
A solution of 1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-carbaldehyde (Example 45, 0.050 g, 0.234 mmol) and MeONH2. HCl (0.020 g, 0.242 mmol) in EtOH (5 mL) and pyridine (5 mL) was refluxed for 20 h. The reaction mixture was then evaporated to dryness and the residue was taken up in H2O and extracted with EtOAc several times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-1% MeOH in CHCl3 to give 0.036 g (63%) of the (E) and 0.013 g (23%) of the (Z) isomers. (Z) isomer: 1H NMR (DMSO-d6) δ 3.54-3.58 (m, 2H), 3.96 (s, 3H), 4.43 (bs, 2H), 7.27 (t, 1H, J=9.0 Hz), 7.89-7.92 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 8.35-8.39 (m, 1H). HRMS calcd for C13H13N3O2 (M+) 243.1008, found 243.1020. Anal. (C13H13N3O2.0.1 H2O.0.1 EtOAc) C, H, N. (E) isomer: 1H NMR (DMSO-d6) δ 3.55 (bs, 2H), 3.87 (s, 3H), 4.37 (bs, 2H), 7.27 (t, 1H, J=7.5 Hz), 7.75 (s, 1H), 7.91 (d, 1H, J=7.5 Hz), 8.24 (d, 1H, J=7.5 Hz), 8.34-8.38 (m, 2H). HRMS calcd. for C13H13N3O2 (M+) 243.1008, found 243.1016. Anal. (C13H13N3O2.0.25 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:21][CH2:20][N:19]([C:31](=[O:33])[CH3:32])[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCNC3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(C)=O)C3)cc12
Reaction time: 16 h

Procedure:
To a suspension of Example 59F (50 mg, 0.130 mmol) and triethylamine (0.091 mL, 0.651 mmol) in dichloromethane (2 mL) was added acetyl chloride (0.195 mL, 0.195 mmol) at room temperature. The mixture was stirred for 16 hours, concentrated, and purified by reverse phase flash chromatography (silica gel-C18, 15-60% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.95 (d, J=4.1 Hz, 3H), 1.98-2.40 (m, 3H), 3.23-3.42 (m, 2H), 3.45-3.60 (m, 2H), 3.73 (s, 3H), 3.77-3.96 (m, 2H), 6.11 (dd, J=10.4, 1.7 Hz, 1H), 7.08 (dd, J=5.1, 1.6 Hz, 1H), 7.15-7.34 (m, 3H), 8.20 (d, J=5.1 Hz, 1H), 11.81 (s, 1H). MS (ESI+) m/z 354.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][C:27]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCC1)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at o@C for 30 min. Cyclohexyl acetic acid 0.72 g and WSC 1.35 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 25 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclohexylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.38 g and refluxed for 1 hour. The reaction mixture was cooled, then added 6N hydrochloric acid and 1N sodium hydroxide thereto, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform acetone methanol=10:1:0.1) to obtain the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)[CH:32]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(-c3cnc4c(c3)C(Oc3cccc(Cl)c3)CCN4)ccn2)CC1
Yield: 36 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (25 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a white foam (36% yield). LCMS: m/z=436.06 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.24-2.40 (m, 1H), 2.35 (s, 3H), 2.54 (t, J=4.9 Hz, 4H), 3.4-3.51 (m, 1H), 3.57-3.68 (m, 5H), 5.27 (bs, 1H), 5.38 (t, J=3.4 Hz, 1H), 6.64 (s, 1H), 6.73 (dd, J=1.0 and 5.2 Hz, 1H), 6.90 (dd, J=2.2 and 8.3 Hz, 1H), 6.95-7.03 (m, 1H), 7.04-7.08 (m, 1H), 7.22-7.28 (m, 1H), 7.57 (d, J=1.9 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.31 (d, J=2.2 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]1[CH2:19][CH2:20][CH2:21][C:22](=[O:23])[C:14]1=[C:13]2[CH3:24].BrBr>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]1[CH2:19][CH2:20][CH:21]([Br:1])[C:22](=[O:23])[C:14]1=[C:13]2[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c2n(c3ccc(Br)cc13)CCCC2=O
Agent: BrBr
Solvent: ClCCl
Product: Cc1c2n(c3ccc(Br)cc13)CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aged N-bromosuccinimide (4.89 g, 27.5 mmol) was added in small portions (over 15 min) to a solution of 2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 8, 5.0 g) in methylene chloride (100 mL) and stirring at room temperature was continued for 30 min. This crude mixture was then protected against light, and a solution of bromine (2 mL) in methylene chloride (200 mL) was added very slowly from a dropping funnel. The reaction mixture was washed successively with cold water, 5% sodium bicarbonate, and water again. After drying (MgSO4) and filtration, the solvent was evaporated, and the title compound was crystallized from chloroform, mp 156° C.; yield 6.6 g; Anal. Calcd for C13H11Br2NO: C, 43.72% H, 3.10% N, 3.92% and Found: C, 43.35% H, 3.00% N, 3.99%.
Reaction SMILES: [Cl:1][C:2]([O:5]C=O)(Cl)Cl.[CH2:8]([NH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:9]=[CH2:10].C(N(CC)CC)C>ClCCl>[CH2:8]([N:11]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]([Cl:1])=[O:5])[CH:9]=[CH2:10]
Reactant: C=CCNC1CCCC1
Reactant: O=COC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C(=O)Cl)C1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
790 mg (0.48 ml, 3.99 mmol) of trichloromethylformate (“diphosgene”) are dissolved in 15 ml of dichloromethane and cooled to 0° C. To this are slowly added dropwise 1.00 g (1.17 ml, 7.986 mmol) of allyl(cyclopentyl)amine and 1.21 g (1.67 ml, 12.0 mmol) of triethylamine, and the mixture is left to stir at room temperature overnight. For workup, the reaction solution is poured into ice-water, extracted three times with dichloromethane, dried over MgSO4 and concentrated. The crude product is employed directly in the next stage.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][C:19](=[O:21])[CH3:20])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(OC(C)C)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Cc1cc(OC(C)C)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-isopropyloxy-2-methylpyridine (687 mg) in tetrahydrofuran (7 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 3.34 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (0.549 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(4-isopropyloxypyridin-2-yl)-propan-2-one (652 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])[CH3:3].O.[NH2:24][NH2:25].O>C(O)C>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][C:10]([NH:24][NH2:25])=[O:11])([CH3:4])[CH3:3]
Reactant: CCOC(=O)COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Yield: 88.1 %

Procedure:
A solution of ethyl [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]acetate (2.5 g, 8.1 mmol) and hydrazine monohydrate (1.2 mL, 24.3 mmol) in ethanol (40 mL) is heated at 65°-75° C. for 8 hours. The reaction mixture is cooled and poured into 500 mL of water. The solids are filtered and washed twice with water. The white solid is dried overnight at 50° C. in vacuo to give 2.1 g (87%) of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]-acetic acid hydrazide; mp 141.0°-142.5° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>ClCCl>[S:13]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCOc1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2ccccn2)cc1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
5 ml of pyridine and 7 g of p-toluenesulfonyl chloride were added to a solution of 6.5 g of the compound obtained in Example 3a in 20 ml of dichloromethane and then the mixture was stirred for 4 hours. The organic layer was washed with 10% aqueous citric acid and then with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 6.57 g of the title compound (yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]2[CH:38]=[C:34]([CH3:33])[N:35]=[CH:36]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: Cc1c[nH]cn1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)cn1
Yield: 32.1 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylimidazole (0.48 g), and dimethylformamide (25 ml), the title compound (0.38 g) was obtained as an amorphous solid, MS, m/z: 403.3 (M+H)+.