Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].C(=O)(O)[O-].[Na+]>CO>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:7]1[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]1(=[O:23])=[O:22]
Reactant: O=S1(=O)N(c2ccccc2F)Cc2ccccc2N1CCCBr
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNCCCN1c2ccccc2CN(c2ccccc2F)S1(=O)=O
Yield: 40 %

Procedure:
1-(3-bromopropyl)-3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.15 g, 0.38 mmol) and an 33% MeNH2 in MeOH (15 mL) was stirred in a sealed tube at room temperature for 16 hours. The reaction was poured into saturated aqueous sodium bicarbonate (20 mL), extracted with ethyl acetate (20 mL), and dried over anhydrous sodium sulfate. The organics were concentrated onto silica gel. Purification via Isco (0-100% dichloromethane containing 15% ammonia in methanol/dichloromethane) followed by treatment with 1 N hydrochloric acid in ether gave 3-[3-(2-fluorophenyl)-2,2-dioxido-3,4-dihydro-1H-2,1,3-benzothiadiazin-1-yl]-N-methylpropan-1-amine (0.056 g, 40%) as an off-white amorphous solid:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[K].[CH2:18](Br)[CH:19]=[CH2:20]>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[S:16][CH2:20][CH:19]=[CH2:18])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Reactant: C=CCBr
Agent: [K]
Solvent: CCO
Product: C=CCSc1nnsc1-c1ccc(C(C)(C)C)cc1
Yield: 72.8 %

Procedure:
A solution of 1.45 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt in 50 ml of ethanol was stirred overnight with 3.0 g of allyl bromide. The solvent was removed in vacuo, the residue taken up in ether, filtered and concentrated in vacuo. The residual oil was dissolved in a small amount of dichloromethane and purified on thick layer silica gel plates, eluting with the same solvent. The active fraction gave 1.225 g of the desired compound as a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 1.39 (s, 9H, t-butyl); 3.98 (bd, 2H, SCH2); 5.05 (bd, 1H, CH=); 5.20 (bd, 1H, =CH); 5.87 (m, 1H, CH2CH=); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (neat): 1640(w); 1615(w); 1525(w); 1480(w); 1475(w); 1450(w); 1410(w); 1370(w); 1270(w); 930(s); 820(s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].C[O:11][C:12](OC)(N(C)C)[CH3:13]>CN(C=O)C>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9])[C:12]([CH3:13])=[O:11]
Reactant: Cc1ccncc1C#N
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccncc1C#N
Yield: 68.7 %

Procedure:
A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) and N,N-dimethylacetamide dimethylacetal (5.4 g, 40.6 mmol) in dry DMF (20 ml) was stirred at 130 for 7 h. The volatiles were removed in vacuo to afford a dark oil which solidified on standing. This material was chromatographed (SiO2; 50% EtOAc/Hexane—100% EtOAc) affording the title compound as an off-yellow solid (3.73 g, 69%). δH (CDCl3) 8.87 (1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s) and 2.36 (3H, s); m/z (ES+, 70V) 161 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].C([N-]C(C)C)(C)C.[Li+].[N:25]1[N:26]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:43][CH3:44])[C:37](N(OC)C)=[O:38])=[CH:32][CH:31]=2)[N:27]=[CH:28][CH:29]=1>C1COCC1>[N:25]1[N:26]([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:43][CH3:44])[C:37]([C:12]3[O:11][C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)=[CH:14][CH:13]=3)=[O:38])=[CH:34][CH:35]=2)[N:27]=[CH:28][CH:29]=1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2nccn2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-n4nccn4)cc3)o2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.20 g, 0.71 mmol) in anhydr THF (10 mL) under argon in an oven-dried flask cooled to −78° C. was added lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 0.43 mL, 0.85 mmol) dropwise. After stirring for 1 hr at −78° C., a solution of 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.195 g, 0.71 mmol) in THF (2 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4Cl and EtOAc was added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (30% EtOAc-hexanes) provided 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a yellow solid (0.07 g, 10% yield). MS: m/z 497.9 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH:8]([C:21](OCC)=[O:22])[N:7]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:15]1([S:12]([N:10]2[CH2:11][CH:6]([CH2:4][OH:3])[N:7]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:8]([CH2:21][OH:22])[CH2:9]2)(=[O:14])=[O:13])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccccc2)CC(C(=O)OCC)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CC(CO)N(Cc2ccccc2)C(CO)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of the above described (2SR,6SR)-4-benzenesulfonyl-1-benzyl-piperazine-2,6-dicarboxylic acid diethyl ester (7.0 g, 15 mmol) in tetrahydrofuran (165 ml) at 23° C. was added a solution of lithium aluminum hydride in tetrahydrofuran (c=1 mol/l, 45.6 ml, 45.6 mmol) and the mixture was stirred at 70° C. for 1 h. Then the reaction was cooled to 0° C., water (1.75 ml) was added very slowly, then NaOH 15% (1.75 ml) and water (5.24 ml). The mixture was stirred at 23° C. for 1.5 h, the precipitate was filtered off, washed with tetrahydrofuran and the organic layer was evaporated totally to give the title compound as a white solid (4.45 g, 78%), MS (ISP) m/e=377.3 [(M+H)+].
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34]>C(Cl)Cl>[CH2:32]([S:35]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5]1)(=[O:37])=[O:36])[CH2:33][CH3:34]
Reactant: CCCS(=O)(=O)Cl
Reactant: N#Cc1ccc(-n2nnnc2CN2CCNCC2)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.2 %

Procedure:
4-[5-(1-piperazinylmethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Example 101, 50 mg, 0.15 mmol) was dissolved in DCM and treated with triethylamine (41 μL, 0.29 mmol) followed by 1-propanesulfonyl chloride (20 μL, 0.18 mmol). The mixture was stirred at ambient temperature under argon for 2.5 hours. The reaction mixture was partitioned between water and DCM (5 mL each) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted with further DCM (2×5 mL). The combined DCM extracts were concentrated in vacuo to give the title compound as a pale cream solid (62 mg).
Reaction SMILES: [OH:1][C:2]1([CH3:30])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N+:12]([O-])=[C:11]3[CH2:19][CH2:20][CH2:21][C:10]=23)[CH2:4][C@H:3]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[CH3:31][C:32]([O:34]C(C)=O)=[O:33]>>[C:32]([O:34][CH:19]1[C:11]2=[N:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]([N:5]3[CH2:6][C@H:7]([CH3:8])[C:2]([OH:1])([CH3:30])[C@H:3]([NH:22][C:23]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:29])[CH2:4]3)=[C:10]2[CH2:21][CH2:20]1)(=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (390 mg, 0.92 mmol) and Ac2O (2 mL) was stirred at 90° C. for 1 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The mixture was neutralized with aq. NaHCO3 and then extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 20-80% EtOAc in hexanes to give the desired product as a yellow oil (196 mg, 55% in 2 steps). LCMS calc. for C22H33N4O7 (M+H)+ m/z=465.2. found 465.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])[C:9]=1[CH3:10])[CH:5]=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])[C:9]=1[CH3:10])[CH2:5][NH:19][CH:16]1[CH2:18][CH2:17]1
Reactant: COC/C=C/c1cc(C=O)cc(Br)c1C
Reactant: NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: COC/C=C/c1cc(CNC2CC2)cc(Br)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-5-[(1E)-3-methoxy-1-propen-1-yl]-4-methylbenzaldehyde (1 eq.) from the previous step and cyclopropylamine (2 eq.) were combined in CH2Cl2 (0.1 M). To this was then added MgSO4 (1 eq.) and the resulting suspension was stirred at RT for 20 h. The insolubles were then removed via filtration through a pad of celite and the filtrate was concentrated in vacuo. The crude imine thus obtained was then re-taken up in MeOH (0.1 M). To this solution was added sodium borohydride (1.5 eq.) portionwise and the resulting mixture was stirred at 0° C. for 30 min, then at RT for 2 h. The reaction was quenched by stirring with 2 N aq. HCl for 25 min, basified with 1 N aq. NaOH and concentrated in vacuo. The residue was extracted with ether from water, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a colorless oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])=[CH:19][CH:18]=1
Reactant: OCCO
Reactant: Clc1ccc(C(=CCBr)c2ccc(Cl)cc2)cc1
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of n-butyllithium in hexanes (15.0 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (30 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo-1,1-bis(4-chlorophenyl)-1-propene (13.0 g, 38 mmol, prepared similarly to the method described in Example 26) was added and the reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic extracts was dried (Na2SO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (200 g) using a mixture of n-heptane and ethyl acetate (3:2) as eluent provided 8.1 g (66%) of 2-(3,3-bis-(4-chlorophenyl)-2-propen-1-yloxy)ethanol.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:11][C:12]1[CH:17]=[C:16]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1cccc(N)c1
Temperature: 80 °C

Procedure:
A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3-aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in dimethoxyethane (50 ml) and 2M sodium carbonate solution (25 ml) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 ml) and water (400 ml). The organics were washed with brine (400 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (0-25%) gave 3′-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid (9.5 g, 98%): δH (400 MHz, CDCl3) 3.79 (2H, br), 6.75 (1H, ddd, J 8, 3 and 1), 6.84 (1H, dd, J 3 and 3), 6.92 (1H, dd, J 8 and 3), 7.25 (1H, dd, J 8 and 8), 7.40 (1H, ddd, J 8, 8 and 1), 7.50 (1H, dd, J 8 and 1), 7.62 (1H, ddd, J 8, 8 and 1), 7.73 (1H, dd, J 8 and 1).
Reaction SMILES: [N+]([O-])(OCCCCC)=O.[CH:10]([Br:13])(Br)Br.NC1[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=1>>[Br:13][C:10]1[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=1
Reactant: COC(=O)c1cnc(N)s1
Reactant: BrC(Br)Br
Agent: CCCCCO[N+](=O)[O-]
Product: COC(=O)c1cnc(Br)s1
Temperature: 97.5 °C

Procedure:
A mixture containing 100 g. of amyl nitrate and 600 ml. of bromoform is warmed to 70° C and then a total of 100 g. of 2- amino-5-methoxycarbonylthiazole is added portionwise with rapid stirring while maintaining the temperature at about 95-100° C. The mixture is then stirred for an additional 10 minutes at this temperature and then the bromoform is distilled off under vacuum. The residue is chromatographed on silica gel yielding 2-bromo-5-methoxycarbonylthiazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[C:16]([O:15][C:13](=[O:14])[CH2:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCc1ccccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccccc1CC#N
Reaction time: 12 h
Yield: 97.5 %

Procedure:
To a mixture of 2.92 g of (2-hydroxyphenyl)acetonitrile, 4.71 g of tert-butyl bromoacetate and 110 mL of DMF was added 6.06 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 5.29 g of tert-butyl[2-(cyanomethyl)phenoxy]acetate as a yellow oily substance.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CSc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(SC)cc32)CC1

Procedure:
In accordance with the general procedure described in the foregoing Examples, 14.0 grams of 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 15.3 grams of lauroyl chloride (dodecanoyl chloride) in a mixture of benzene and chloroform. In this manner, 8-methylthio-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was obtained. The pure base was a viscous oil which formed a crystalline di(hydrogen maleate) that had a melting point of 121°-122°C, after recrystallization from acetone.
Reaction SMILES: [CH3:1][C:2]1([CH3:45])[CH2:7][O:6][CH:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[C:32]([NH:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH:37]([C:41]([O:43]C)=[O:42])[CH2:36]3)=[O:33])=[CH:14][CH:13]=2)[O:4][CH2:3]1.Cl>CO.C1COCC1.[OH-].[Na+]>[C:41]([CH:37]1[CH2:38][CH2:39][CH2:40][CH:35]([NH:34][C:32]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=2[O:21][CH2:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH:5]3[O:4][CH2:3][C:2]([CH3:45])([CH3:1])[CH2:7][O:6]3)=[CH:13][CH:14]=2)[C:26]([O:28][CH3:29])=[O:27])=[O:33])[CH2:36]1)([OH:43])=[O:42]
Reactant: COC(=O)c1ccc(OCCCc2ccc(OCCCC3OCC(C)(C)CO3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCc2ccc(OCCCC3OCC(C)(C)CO3)cc2)c(C(=O)NC2CCCC(C(=O)O)C2)c1
Reaction time: 15 h
Yield: 77.9 %

Procedure:
A solution of 70.0 mg of methyl 4-(3-{4-[3-(5,5-dimethyl-1,3-dioxan-2-yl)propoxy]-phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate in 1 ml each of methanol, THF and 2 molar sodium hydroxide solution is stirred at a temperature of 60° C. for 2 hours. Then 1.1 ml of 2 molar hydrochloric acid are added, and the reaction mixture is left to stand open at room temperature for 15 hours. A precipitate separates out and is filtered off with suction and washed with water. If the precipitation is incomplete, extraction with ethyl acetate is possible. The organic extract is dried over anhydrous sodium sulphate and evaporated. 53.3 mg of a solid are obtained.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:31]([CH3:32])=[C:30]([Br:33])[C:29](=[O:34])[N:28]([CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH3:40])=O)(C)(C)C.[Cl:41]CCl>Cl>[ClH:41].[Br:33][C:30]1[C:29](=[O:34])[N:28]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH:13]([CH3:14])[NH:8][CH:9]([CH3:40])[CH2:10]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[C:31]=1[CH3:32]
Reactant: ClCCl
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)C(C)C4)cn3)ncc12
Agent: Cl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)NC(C)C4)cn3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051 g, 0.083 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl (2 mL) was added and the mixture was stirred at room temperature for 2 hours. This mixture was concentrated and allowed to sit for 10 days, it was then dissolved in 2 N HCl (2 mL) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.039 g, 71.4%). 1H NMR δ (400 MHz, DMSO-d6) 9.51 (m, 1H), 9.02 (m, 1H), 8.98 (s, 1H), 8.07 (s, 1H), 7.83 (s, 2H), 5.90 (m, 1H), 3.85 (d, J=11.2 Hz, 2H), 3.35 (m, 2H), 2.76 (dd, J=12.0, 12.0 Hz 2H), 2.58 (s, 3H), 2.14 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H), 1.58 (m, 2H), 1.28 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:12][C:11]=2[N+:21]([O-])=O)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[NH2:21][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:24])([F:1])[CH2:3][CH2:4]1
Reactant: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1

Procedure:
Following the same procedure as in Step D of Example 4 using methyl (4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)carbamate (200 mg, 0.583 mmol) and a catalytic amount of 10% Pd/C in 20 mL of EtOAc. Yield: 185 mg (99%). MS (ESI) (M+H)+ 314.29.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:17])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=Cc1ccccc1
Product: OC(c1ccccc1)c1cnc(Cl)nc1Cl
Yield: 79 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and benzaldehyde (Aldrich) in 79% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 7.36 (m, 5H), 6.06 (d, 1H, J=3.0 Hz), 2.48 (br m,1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl
Product: CN1CCN(c2cnc(-c3cc(Cl)cc(Cl)c3Cl)c(N)n2)CC1
Temperature: 140 °C

Procedure:
2-Amino-6-chloro-3-(2,3,5-trichlorophenyl)pyrazine (0.215 g ,7.0×10−3 mole) Example I Route A and 1-methylpiperazine (5 ml, Aldrich), were heated at 140° C. for 1 hr. The mixture was evaporated in vacuo and the residue was purified by ‘flash chromatography’ eluting with ethanol:dichloromethane, 0-4%. The product was dissolved in the minimum of dichloromethane and hexane (10 ml), added slowly to give yellow needles. Yield 0.247 g (95%), M.p. 185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]([CH3:25])[S:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[CH3:24])(=[O:14])=[O:13])[NH:7][C:6]=2[C:26]=1[C:27]([O:29]CC)=[O:28].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]([CH3:25])[S:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[CH3:24])(=[O:14])=[O:13])[NH:7][C:6]=2[C:26]=1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)c1c(F)ccc2nc(CN(C)S(=O)(=O)c3c(C)cc(OC)cc3C)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3ccc(F)c(C(=O)O)c3[nH]2)c(C)c1
Yield: 20 %

Procedure:
Ethyl 6-fluoro-2-((4-methoxy-N,2,6-trimethylphenylsulfonamido)methyl)-1H-benzo[d]imidazole-7-carboxylate (F-20) (2.4 mmol, 1 eq.) was hydrolysed with LiOH in THF/H2O (1:1). After the hydrolysis, the solvent was removed completely from the reaction mixture in vacuo and the residue was taken up in water and washed with ethyl acetate. The aqueous phase was adjusted to pH=4 and then extracted with ethyl acetate. The free acid 6-fluoro-2-((4-methoxy-N,2,6-trimethylphenyl-sulfonamido)methyl)-1H-benzo[d]imidazole-7-carboxylic acid (ACI-20) obtained in this way was coupled with 9-pyridin-4-Yl-3,9-diazaspiro[5.5]undecane dihydrochloride (AMN-01) under standard peptide coupling conditions. Yield: 20%