Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[C:28]([O:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][CH2:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:27])[CH3:26])[CH2:6][CH2:7]3)=[O:25])=[C:16]([CH3:24])[CH:17]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)Cc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 28 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (73 mg, 0.30 mmol) in dichloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield the title compound (25 mg, 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[C:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH:31][C:28]1[CH:29]=[N:30][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][CH:27]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1cnc(-c2ccccc2)nc1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2ccccc2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (1.096 g, 4.38 mmol, 1.50 equiv) in dichloromethane (20 mL), 2-phenylpyrimidin-5-amine (500 mg, 2.92 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (838 mg, 4.39 mmol, 1.50 equiv), and 4-dimethylaminopyridine (713 mg, 5.84 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The reaction was diluted with 100 mL of water and the resulting mixture was extracted with 3×50 mL of dichloromethane. The organic layers were combined, washed with 1×100 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE:EA:CH2Cl2 (20:1:0-3:1:1). The product was obtained as 150 mg (11%) of a yellow solid.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH3:15][NH:16][C:17](=O)[CH2:18][C:19]1([NH:33][CH3:34])[CH2:28][CH:27]2[N:22]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:21][CH2:20]1>C1(C)C=CC=CC=1.C1COCC1>[CH3:34][NH:33][C:19]1([CH2:18][CH2:17][NH:16][CH3:15])[CH2:28][CH:27]2[N:22]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:21][CH2:20]1
Reactant: CNC(=O)CC1(NC)CCN2CCc3ccccc3C2C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNCCC1(NC)CCN2CCc3ccccc3C2C1

Procedure:
To a 500 ml round bottomed flask with stirring bar, refluxed condenser, dropping funnel and argon inlet was added a solution of sodium bis (2-methoxyethoxy)aluminum hydride (20.63 ml of a 3.4M solution in toluene) and 100 ml of dry THF. This solution was heated at reflux and a solution of the acetamide (5.04 g, 17.54 mmol) from Step B in 100 ml of dry THF was added dropwise over 45 minutes. When the addition was complete the mixture was heated at reflux for 2 hours. The reaction mixture was chilled in an ice bath and quenched with 100 ml of saturated aqueous potassium sodium tartrate solution. The resulting mixture was diluted with ethyl acetate (300 ml) and the layers were separated. The organic phase was washed with an additional 200 ml of tartrate solution and 200 ml of brine. Drying (K2CO3), filtration and removal of the solvent in vacuo left 4.90 g of (2RS,11bSR)-2-methylamino-2-(2-methylaminoethyl)- 1,3,4,6,7,11b-hexahydrobenzo[a]quinolizine as an oil.
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.[CH3:12][C:13]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:14]=1[O:15][CH2:16][C:17](O)=O.[CH2:25]([NH:28][CH:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[O:39][CH3:40])[CH2:30]1)[CH2:26][CH3:27]>>[CH3:40][O:39][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:36]=1[CH2:37][CH2:38][CH:29]([N:28]([CH2:17][CH2:16][O:15][C:14]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:13]=1[CH3:12])[CH2:25][CH2:26][CH3:27])[CH2:30]2
Reactant: Cc1ccc(C)c(OCC(=O)O)c1
Reactant: CCCNC1CCc2c(cccc2OC)C1
Agent: O=C(O)COc1ccccc1
Product: CCCN(CCOc1cc(C)ccc1C)C1CCc2c(cccc2OC)C1

Procedure:
In Example 29, phenoxyacetic acid was replaced by 2,5-dimethylphenoxyacetic acid and (-)-2-(N-n-propylamino)-5-methoxytetralin was replaced by (+)-2-(N-n-propylamino)-5-methoxytetralin. The crude mixture was subjected to flash chromatography (Silica: 9:1 pet ether/EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ 7.1-6.6(m, 6H), 4.0(t, 2H), 3.8(s, 3H), 2.3(s, 3H), 2.15(s, 3H), 0.9(t,3H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][NH2:58])=[CH:53][CH:52]=1.Cl>C1COCC1>[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][NH:58][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:6]([O:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[N:7][CH:8]=2)=[CH:53][CH:52]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccco2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(NNc1ccc(F)cc1)c1cnc(OC2CCC2)c(-c2ccco2)c1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In a 5 mL round-bottomed flask the above prepared 6-cyclobutoxy-5-furan-2-yl-nicotinic acid (0.050 g, 174 μmol, Eq: 1.00) was combined with THF (2 mL) to give a colorless solution. TBTU (83.6 mg, 260 μmol, Eq: 1.5) and N,N-diisopropylamine (112 mg, 152 μL, 868 μmol, Eq: 5) were added. The reaction mixture was stirred for 10 min at RT before (4-fluorophenyl)-hydrazine hydrochloride (33.9 mg, 208 μmol, Eq: 1.2) was added and the reaction allowed to proceed at RT overnight. The mixture was poured into 15 mL 1 M HCl and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 1 M NaOH, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) to yield 40 mg of the title compound as white solid; MS (EI) 368.4 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[C:18]1=[O:28])[CH3:15].O>C(OCC)C>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[C:18]1([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:28])[CH3:13]
Reactant: Brc1cccnc1
Reactant: COc1ccc2c(c1)CC(CN(C)C)C2=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)CC(CN(C)C)C2(O)c1cccnc1
Reaction time: 0.67 h

Procedure:
47 ml of n-butyllithium solution (1.6 mol./l in n-hexane) were added dropwise at a temperature of from −30 to −35° C. to a solution of 7.3 ml of 3-bromopyridine in about 125 ml of diethyl ether p.a. After a further 20 minutes at that temperature, 11 g of 2-dimethylaminomethyl-5-methoxy-indan-1-one, dissolved in diethyl ether p.a., were added dropwise, with continued cooling, stirring was continued for 40 minutes at that temperature, and heating was carried out overnight to room temperature. Then 46 ml of water were added at from −10 to 0° C., the phases were separated, the aqueous phase was extracted with diethyl ether (monitoring by thin-layer chromatography), and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The resulting crude product was chromatographed on silica gel with ethyl acetate/25% ammonia solution (v/v=98:2). 7.06 g of 2-dimethylaminomethyl-5-methoxy-1-pyridin-3-yl-indan-1-ol were obtained and were dissolved in about 125 ml of 2-butanone p.a. and converted into the corresponding hydrochloride with about 0.3 ml of water and about 4.2 ml of chlorotrimethylsilane, while cooling with ice; the hydrochloride was filtered off with suction with the exclusion of air and dried in vacuo (about 50 mbar) (yield 6.79 g, mixture of the two diastereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:36])[C:20]=2[CH:21]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)C(F)(F)F)[CH:24]([F:35])[CH2:23][CH2:22]2)[N:13]=1.Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:36])[C:20]=1[CH:21]1[CH2:22][CH2:23][C@@H:24]([F:35])[C@H:25]([NH2:28])[CH2:26][CH2:27]1)=[O:37]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@H](F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)cycloheptyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (Diastereomer 2) (28 mg, 0.042 mmol) in MeOH (2 mL) was added a solution of HCl in dioxane (4 M, 1.1 mL, 4.24 mmol) and the mixture was stirred at room temperature for 18 hr. The solvent was removed under reduced pressure and the residue was dissolved in MeOH/water (3 mL/3 mL), treated with K2CO3 (29 mg, 0.21 mmol) and heated at 60° C. for 18 hr. The MeOH was removed under reduced pressure and the aqueous residue was extracted with 5% MeOH/DCM (2×40 mL). The organic layers were combined, passed through a phase separation cartridge and concentrated under reduced pressure to give 358 (Diastereomer 2) as an off-white solid (17 mg, 86% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.76 (s, 1H), 7.34-7.29 (m, 1H), 7.03 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.47-4.29 (m, 1H), 3.83 (s, 3H), 3.23-3.12 (m, 1H), 2.86-2.75 (m, 1H), 2.25-1.84 (m, 6H), 1.60-1.40 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 465 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:41])([F:40])[C:24]([C:26]1[S:30][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[CH:28][CH:27]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][CH:39]=[C:31]([C:29]5[S:30][C:26]([C:24](=[O:25])[C:23]([F:22])([F:40])[F:41])=[CH:27][CH:28]=5)[CH:32]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(CN)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc(C(=O)C(F)(F)F)s3)c2)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 4 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (8.5 mg, yield 4%). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (m, 1H), 8.14-8.13 (m, 2H), 8.00-7.86 (m, 4H), 7.82-7.77 (m, 1H), 7.70 (m, 1H), 7.60-7.56 (m, 1H), 7.48-7.46 (m, 2H), 3.50 (m, 2H), 3.39-3.17 (m, 4H), 2.57 (m, 3H), 2.43 (m, 2H), 2.08 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:47]1([C:53]2[O:57][C:56]([C:58]([NH2:61])([CH3:60])[CH3:59])=[N:55][N:54]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([NH:61][C:58]([C:56]3[O:57][C:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[N:54][N:55]=3)([CH3:60])[CH3:59])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(C(=O)O)ncc2C2CC2)COC1
Reactant: CC(C)(N)c1nnc(-c2ccccc2)o1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(COc2cc(C(=O)NC(C)(C)c3nnc(-c4ccccc4)o3)ncc2C2CC2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of the acid 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinic acid (20 mg, 76.0 μmol) in dichloromethane (1 ml) was added DIPEA (24.5 mg, 33.2 μl, 190 μmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (23.1 mg, 83.6 μmol). The reaction is stirred for 30 minutes at room temperature followed by addition of 2-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-amine (CAN 68176-04-5, 15.4 mg, 76.0 μmol) and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane (5 mL) and washed with a 0.2M aqueous solution of hydrochloric acid (3×10 mL) and brine (15 mL). The organic phase is dried over magnesium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (24.3 mg, 71%). MS (ESI, m/z): 449.7 (M+H+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]3[C:35]([C:36]=2[NH2:37])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:27]3[CH:28]=[N:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]=3[NH:37][C:1]2=[O:2])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(NC2CCN(Cc3ccccc3)CC2)cnc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
22.6 g (139 mmol) 1,1′-carbonyldiimidazole were added to a solution of 9.0 g (27.1 mmol) N3-(1-benzylpiperidin-4-yl)-quinoline-3,4-diamine in 100 mL DMF. The mixture was heated to 100° C. and stirred for 1.5 h at this temperature. After cooling the reaction mixture it was poured onto 300 mL water. The precipitated solid was filtered off, washed with water and dried at 30° C. i. vac. The residue was triturated with diethyl ether, suction filtered and the solid product was dried i. vac.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a 0° solution of 15 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 17.48 g of methanesulfonyl chloride in 100 ml of methylene chloride. The mixture is stirred at 0° C. for 1 hour followed by stirring at room temperature for 3 hours. The reaction is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with saturated sodium chloride and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10% methyl alcohol/ethyl acetate) to give 19.84 g of the desired product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]1[N:16]=[C:17]2[C:22](=[N:23][CH:24]=1)[N:21]=[CH:20][N:19]([CH3:25])[C:18]2=[O:26]>COCCO>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[N:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]=[CH:20][N:19]([CH3:25])[C:18]3=[O:26])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1cnc2ncc(Br)nc2c1=O
Solvent: COCCO
Product: Cn1cnc2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1=O
Temperature: 100 °C
Yield: 91.4 %

Procedure:
To a stirred solution of 1-Boc-piperazine (18.9 g, 101.4 mmol) in 2-methoxyethanol (100 mL) was added 6-bromo-3-methyl-3H-pteridin-4-one (11.6 g, 48 mmol; see Example 16 (c) above) and the resulting suspension was heated for 3 hours at 100° C. The reaction was then cooled in an ice-water bath and the precipitate that formed was collected, washed with cold MeOH, and dried to afford 4-(3-methyl-4-oxo-3,4-dihydro-pteridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (15.2 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.48 (s, 9H), 3.57-3.61 (m, 4H), 3.62 (s, 3H),3.78-3.82 (m, 4H), 8.07 (s, 1H), 8.56 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ28.38, 34.42, 44.40, 80.38, 130.64, 137.93, 145.53, 147.04, 152.91, 154.61, 160.89.
Reaction SMILES: CS(O[CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)(=O)=O.N12CCC(CC1)C(O)C2.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][SH:30])=[CH:27][CH:26]=1.[H-].[Na+]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:30][CH:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH2:7]2)=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)OC1CN2CCC1CC2
Reactant: COc1ccc(CS)cc1
Agent: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CSC2CN3CCC2CC3)cc1

Procedure:
The procedure described in preparation 6-(2) was repeated, but using 3.7 g of 3-methanesulfonyloxyquinuclidine (prepared by the methanesulfonylation of 3-quinuclidinol), 3.0 ml of 4-methoxybenzyl mercaptan and 0.942 g of sodium hydride (as a 55% w/w suspension in mineral oil), to afford 1.74 g of the title compound as an oil.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[O:4]=[C:3]1[CH2:2][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][C:7]=2[NH:6]1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)NC(=O)CO2
Reaction time: 1 h
Yield: 90 %

Procedure:
Chloroacetyl chloride (1 equiv.) was added at room temperature to a mixture of methyl (3-amino-4-hydroxyphenyl)acetate (5.5 mmol) and sodium hydrogen carbonate (1.1 equiv.) in ethyl acetate (5 ml)/water (5 ml). The reaction mixture was stirred for 1 h, then the phases were separated and the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in DMF (11 ml); activated potassium carbonate was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was again washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane). Yield: 90%
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2,5-dichlorobenzenesulfonyl chloride (2.46 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as apale yellow solid (1.65 g, 51%). 1H-NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.55 (s, 2H), 6.56 (s, 2H), 6.46 (s, 1H), 5.29 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: ClCCc1nnn[nH]1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCc2nnn[nH]2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 5-(2-chloroethyl)-1H-tetrazole.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:24])=O>ClCCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([Cl:24])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Yield: 102 %

Procedure:
In 100 ml of 1,2-dichloroethane, 57 g (0.19 mol) of 3,4,5-triacetoxybenzoic acid and 34 g (0.29 mol) of thionyl chloride were reacted at 60° C. for 2 hours. The excess thionyl chloride and 1,2-dichloroethane were distilled away under reduced pressure to obtain 61 g of the desired product.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CO>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:14]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccccn1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(N)ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
Tin(II) chloride dihydrate (6.77 g, 30.0 mmol) and 2-(2-methoxy-4-nitrophenyl)pyridine (2.30 g, 10.0 mmol) were combined in MeOH (100 mL) and stirred at reflux for 18 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was then partitioned with EtOAc (200 mL) and 1N aqueous NaOH (100 mL). The aqueous layer was washed with EtOAc (3×75 mL), and the combined EtOAc layers were back-extracted with H2O (100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by SiO2 chromatography, eluting with 2:1 EtOAc:hexanes to afford 3-methoxy4-pyridin-2-ylaniline as an amber oil. 1H-NMR (CDCl3, 300 MHz) δ 8.63 (m, 1H), 7.78 (d, 1H), 7.57-7.67 (m, 2H), 7.04-7.13 (m, 1H), 6.34-6.41(dd, 1H), 6.26 (d, 1H), 3.72-3.92 (s, 2H), 3.72 (s, 3H).