Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1/[CH:8]=[N:9]/[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cl-].[NH4+].[Cu]I>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:9]=[CH:8][C:7]=12
Reactant: Fc1ccc(N/N=C/c2c(Br)cncc2Br)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Temperature: 120 °C

Procedure:
A mixture of N-[1-(3,5-dibromopyridin-4-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine (2.0 g, 5.4 mmol), CuI (50.0 mg, 0.260 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.200 mL, 1.27 mmol), and K2CO3 (1.4 g, 0.010 mol) in NMP (10 mL) was warmed at 120° C. for 30 minutes. The reaction was monitored by HPLC-MS indicating the desired mass. The mixture was diluted with aqueous ammonium chloride (100 mL) and the resulting solid collected by filtration. The solid was dissolved in hot ethyl acetate (EtOAc), dried over magnesium sulfate, treated with activated carbon, filtered through diatomaceous earth and concentrated. The residue was passed through a pad of silica gel eluting with dichloromethane to afford 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[C:11]([O:12][C@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.CN.CO>>[F:30][C:2]([F:1])([F:31])[C:3]1[C:11]([O:12][C@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH2:19])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2C(F)(F)F)C1
Agent: CN
Solvent: CO
Product: N[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2C(F)(F)F)C1
Yield: 31.2 %

Procedure:
A mixture of the crude product 2-{trans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (0.324 g) and a 30% methylamine/methanol solution (15 ml) was stirred at 90° C. for 3 hours. The solvent was distilled off and the residue solid was purified by elution by a silica gel column chromatography (chloroform/methanol=20:1→chloroform/methanol/triethylamine=10:1:1) to obtain trans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine (70.4 mg, 16%, two steps).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][N:11]1C[CH2:15][CH2:14][CH2:13][CH:12]1CO>C(O)C>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[CH3:10])=[O:5])[CH3:9]
Reactant: CCOC(=O)CN(C)C
Reactant: CN1CCCCC1CO
Solvent: CCO
Product: CN(C)CC(=O)OCC1CCCCN1C

Procedure:
A mixture of 75 g of ethyl N,N-dimethylglycinate, 75 g of 1-methyl-2-piperidylmethanol and 1 g of titanium tetra(n-butoxide) was heated at 45° C. until the amount of ethanol collected indicated the reaction was complete. After cooling a small amount of water was added, the mixture was filtered, and the filtrate was distilled under reduced pressure to provide N-methyl-2-piperidylmethyl N,N-dimethylaminoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(Br)c(C=O)c1
Agent: BrB(Br)Br
Product: O=Cc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
To the solution of 2-bromo-5-methoxy-benzaldehyde (10 g, 46.5 mmol) at −78° C. is added BBr3 (25 g, 93.75 mmol) and allowed to warm to room temperature. After 2 h, the reaction is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with water, brine, dried over MgSO4, concentrated and purified by column chromatography to afford 3.6 g of 2-bromo-5-hydroxy-benzaldehyde. To the solution of 2-bromo-5-hydroxy-benzaldehyde (1.45 g, 7.2 mmol in benzene (30 ml) and THF (6 ml) is added 1,3-propanediol (2.74 g, 36 mmol) and TsOH (37 mg, 0.22 mmol). The mixture is refluxed for 24. After cooling down, the solvent is evaporated. The residue is loaded on silica and purified by column chromatography to afford the titled compound (2.3 g) as brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccnc4)c(C(=O)O)s3)c2cc1OC
Yield: 6.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and pyridine-3-boronic acid (18.4 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-pyridin-3-yl-thiazole-5-carboxylic acid (2.6 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.68 (br.s., 1 H); 9.07 (d, 1H); 8.85 (s, 1 H); 8.66 (dd, 1 H); 8.31 (dt, 1 H); 7.81 (s, 1 H); 7.55 (ddd, 1 H); 7.40 (s, 1 H); 3.86 (s, 3 H); 3.85 (s, 3 H). MS m/z 383 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].CCN(CC)CC.Cl>CCOC(C)=O>[CH3:39][S:40]([O:21][CH2:20][C:18]1[CH:17]=[C:16]([O:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:15]=[C:14]([CH2:13][N:12]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[S:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:38])(=[O:11])=[O:10])[CH:19]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cc(CO)cc(Oc2ccc(F)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-(4-fluorophenoxy)-5-(hydroxymethyl)benzyl)-2-hydroxybenzenesulfonamide (1.1 g, 1.895 mmol) and methanesulfonyl chloride (0.147 mL, 1.895 mmol) in EtOAc at −30° C. was added Et3N (0.4 mL, 2.87 mmol) under Ar atm. The mixture was stirred for 1 h, but only a small amount of product was produced. Thus, additional methanesulfonyl chloride (0.25 mL) and Et3N (0.6 mL) were added at −30° C. The mixture was slowly warmed to rt, stirred at rt for 2 h and treated with 1N aq HCl and EtOAc. The EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain the desired product as a viscous material (˜1.4 g). This material was used directly for the next step without further purification. 1H NMR (CDCl3): δ 7.61 (d, J=2.8 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.07-6.89 (m, 8H), 6.82 (d, J=1.6 Hz, 2H), 6.63 (s, 1H), 5.06 (s, 2H), 4.37 (s, 2H), 4.34 (s, 2H), 2.97 (s, 3H; MS: (M−H)−=656.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18]Br)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](=[S:28])[S-:27])[CH3:24].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:28][C:26]([N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])=[S:27])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=S)[S-]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)C(=S)SCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
To the solution of 3-(benzyloxycarbonylamino)-N-(2-bromoethyl)propionamide (10 g) in acetone (250 ml), sodium diethyldithiocarbamate trihydrate (6.8 g) in acetone (150 ml) is added and the mixture is stirred for 40 minutes at room temperature. The reaction mixture is filterd and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate (150 ml) and the solution is washed with N hydrochloric acid, N sodium hydroxide, water and saturated sodium chloride solution in the named order. The ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give 10.7 g (89%) of the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>CN(C=O)C.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[CH3:1][N:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCC(N(C)CCc3ccc(Oc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 54 h

Procedure:
A solution of N-methyl-N-[2-(4-phenoxyphenyl)ethyl]-4-piperidinamine (about 0.7 mmol) in DMF (5 mL) and diisopropylethylamine (5 mL) was stirred as methyl 4-(bromomethyl)benzoate (163 mg, 0.71 mmol) was added. The reaction was stirred for 54 hours at ambient temperature. The reaction was diluted with ethyl acetate, washed with brine, dried, and concentrated to give methyl 4-[[4-[methyl[2-(4-phenoxyphenyl)ethyl]amino]-1-piperidinyl]methyl]benzoate; 1H NMR (CDCl3) 7.76 (d, 2H), 7.37 (d, 2H), 7.28 (td, 2H), 7.14 (d, 2H), 7.06 (dt, 1H), 6.95 (dt, 2H), 6.92 (dd, 2H), 3.84 (s, 3H), 3.55 (s, 2H), 2.87 (m, 2H), 2.71 (m, 3H), 2.51 (m, 1H), 2.01 (s, 3H), 1.98 (m, 2H), 1.76 (m, 2H), 1.62 (m, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>CN(C=O)C>[CH3:14][C:11]1([CH3:13])[C:10](=[O:15])[C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:7][CH:6]=2)[O:12]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC1(C)OC(c2ccc(O)cc2)=C(c2ccncc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(c2ccncc2)C1=O
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a room temperature solution of 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 0.9 mol) in DMF (5 mL), K2CO3 (413 mg, 2.98 mol) was added and the reaction mixture was stirred for 30 min. 2-Chloro methyl quinoline (235 mg, 1.09 mol) was then added to the reaction and stirring was continued for 2 h at 85° C. The reaction mixture was then quenched with cold water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2,2-dimethyl-4-(pyridin-4-yl)-5-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (240 mg, 57%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.58-8.54 (m, 2H), 8.42 (d, J=7.8 Hz, 1H), 8.04-7.98 (m, 2H), 7.80 (t, J=7.6 Hz, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.58 (d, J=7.4 Hz, 2 H), 7.30-7.24 (m, 2H), 7.19 (d, J=7.2 Hz, 2H), 5.43 (s, 2H), 1.50 (s, 6H). MS: M+H: m/z=423.0. HPLC: 96%, (Condition-I).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]([CH:13]=O)[C:7]3[CH:8]=[CH:9][CH:10]=[N:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>>[N+:20]([C:23]([CH3:24])=[CH:13][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:12]=2[N:4]2[CH2:3][CH2:2][CH2:1][C:5]=12)([O-:22])=[O:21]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c2n(c3ncccc13)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c2n(c3ncccc13)CCC2)[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
A stirred solution of 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene-8-carbaldehyde (2.3 g) and ammonium acetate (1.05 g) in nitroethane was heated to 100° C. for 2.5 h, cooled to room temperature, and evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the phases separated, the aqueous phase re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane 2:1 to 4:1) to afford 8-(2-nitropropenyl)-2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene as a yellow solid (2.4 g, 80%); MS (EI) 244 (M+H)+, 224, 195, 171; 1H NMR (δ, CDCl3) 8.31 (dd, 1H, J=1,5 Hz), 8.29 (s, 1H), 7.92 (dd, 1H, J=1,8 Hz), 7.16 (dd,1H, J=5,8 Hz), 4.34 (t,2H, J=6 Hz), 3.18 (t,2H, J=8 Hz), 2.72 (dt,2H, J=6,8 Hz), 2.45 (s,3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:30]2[S:34][N:33]=[C:32]([CH3:35])[N:31]=2)=[C:26]([CH:29]=1)[CH:27]=O.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: COc1ccc(-c2nc(C)ns2)c(C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(C)ns2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 19.7 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (110 mg, 0.43 mmol) and 5-methoxy-2-(3-methyl-1,2,4-thiadiazol-5-yl)-benzaldehyde (100 mg, 0.43 mmol) in acetic acid (5 mL) is warmed to 50° C. for 12 hours then at 80° C. for 60 hours. The reaction mixture is cooled to room temperature and poured into water and NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (40 mg, 20%). LCMS (ESMS): m/z 472.20 (M++1)
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH:5]([NH:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH2:23][CH2:22]2)=[O:17])[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.Cl.Cl.[NH2:31][C:32]1[C:36]([NH2:37])=[CH:35][S:34][CH:33]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:37][C:36]1[C:32]([NH:31][C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([CH:5]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH2:23][CH2:22]4)=[O:17])[CH2:4][CH2:3][N:2]([CH3:28])[CH3:1])=[CH:14][CH:13]=2)=[CH:33][S:34][CH:35]=1
Reactant: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)O)cc1
Reactant: Nc1cscc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)Nc2cscc2N)cc1
Yield: 57.6 %

Procedure:
A solution of 4-[1-(2-dimethylaminoethyl)-3-(indan-5-yl)ureidomethyl]benzoic acid (Reference Compound No. 11-1, 77 mg, 0.20 mmol), 3,4-diaminothiophene dihydrochloride (45 mg, 0.24 mmol), N,N-diisopropylethylamine (77 μL, 0.44 mmol) and HATU (90 mg, 0.24 mmol) in DMF (2.0 mL) was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, and then the whole was extracted with ethyl acetate (30 mL) three times. The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel (NH-modified silica gel) column chromatography (chloroform-methanol) to give 55 mg of the title compound as a brown amorphous product. (Yield 58%)
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[C:6]([CH3:21])[NH:5][N:4]=1.[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:16][C@H:14]([C:13]2[N:12]=[C:11]3[CH:17]=[CH:18][N:19]([CH3:20])[C:10]3=[CH:9][C:8]=2[C:7]2[C:6]([CH3:21])=[N:5][NH:4][C:3]=2[CH3:2])[CH3:15])[N:24]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(N)nc(N)c1C#N
Temperature: 120 °C
Yield: 54.9 %

Procedure:
(1S)-1-(6-(3,5-Dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (123 mg, 0.403 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (82 mg, 0.484 mmol), and N-ethyl-N-isopropylpropan-2-amine (211 μL, 1.21 mmol) were combined in acetonitrile (4030 μL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated in vacuo. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30% ACN in water. The fractions containing the desired product were combined, concentrated, and lyophilized to give the title compound as an off-white solid (89 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (d, J=6.35 Hz, 3 H), 1.92 (br s, 3 H), 2.06 (br s, 3 H), 3.82 (s, 3H), 5.20 (br s, 1 H), 6.43 (br s, 2 H), 6.53-6.60 (m, 3 H), 6.96 (br s, 1 H), 7.62-7.69 (m, 2H), 12.36 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C26H22N10, 403; found 403.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.CC1(C)O[C@@H](CO)CO1>>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH3:19])[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Agent: CC1(C)OC[C@H](CO)O1
Product: Cc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine using (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol; LC-MS: tR=0.67 min, [M+1]+=295.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[NH:14]1[CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:14]2[CH2:17][CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and azetidine hydrochloride (68 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, and extraction was carried out twice with dichloromethane (15 mL). Washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (132 mg, yield 78%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]5[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=5)[C:27](=[O:38])[C:14]=4[C:15]([O:16]S(C4C(C)=CC=CC=4)(=O)=O)=[C:9]3[C:8]2=[O:39])=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[F:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]5[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=5)[C:27](=[O:38])[C:14]=4[C:15]([OH:16])=[C:9]3[C:8]2=[O:39])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)Oc1c2c(n3c1C(=O)N(Cc1ccc(F)cc1)CC3)CCN(Cc1ccncc1)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2c(O)c3n(c2CCN1Cc1ccncc1)CCN(Cc1ccc(F)cc1)C3=O

Procedure:
A solution of 8-(4-fluorobenzyl)-2-(4-pyridinylmethyl)-10-toluenesulfonyloxy-3,4,7,8-tetrahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (10 mg, 0.017 mmol) and sodium methoxide (3 mg, 0.052 mmol) in anhydrous methanol (0.5 mL) was heated in an oil bath at 60° C. for one hour. The solution was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the titled compounds.
Reaction SMILES: FC1C=CC(C[O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH:19]([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:12][CH2:11]3)=CC=1>C(O)C.[Pd]>[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH:19]([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:12][CH2:11]2
Reactant: CC(C(N)=O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C(N)=O)N1CCc2cc(O)ccc2C1=O
Reaction time: 8 h
Yield: 105.7 %

Procedure:
2-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide (example 10) (3 g, 8.76 mmol) was solved in dry ethanol (150 mL) and under an argon flow, palladium on charcoal 10% was added (93 mg, 0.0876 mmol). The argon was evacuated and replaced by hydrogen. The reaction mixture was stirred overnight and after evacuation of the hydrogen and replacement by argon the system was opened and the reaction filtrated to remove the palladium and concentrated. After concentration the compound was obtained as a white solid (2.17 g, 100%). MS: m/e=232.8 (M−H+).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C(#N)C>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][Br:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Solvent: O
Solvent: CC#N
Product: BrCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4′-(2-benzylbenzofuran-3-yl)biphenyl-4-methanol (5.01 g, 12.7 mmol) in anhydrous acetonitrile (75 mL) was added dibromotriphenylphosphorane (5.45 g, 12.7 mmol) as a solid portionwise over 15 mins. The reaction was stirred for 2 hours (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the title compound as an off-white solid (4.98 g, 87%): 1H NMR (CDCl3, 300 MHz): δ 7.70 (2H, m, Ar—H), 7.63 (4H, m, Ar—H), 7.50 (3H, m, Ar—H), 7.30 (4H, m, Ar—H), 7.25 (4H, m, Ar—H), 4.57 (2H, s, CH2Br), 4.26 (2H, PhCH2).