Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: NCCO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)NCCO)cc1

Procedure:
The preparation is carried out as in Example 1(a) from 413.3 g (2 mol) of p-methoxybenzenesulphonyl chloride and 128.3 g (2.1 mol) of ethanolamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1.COCCO>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:37][C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([N:30]([CH3:38])[CH3:29])[CH:32]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Reactant: CN(C)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: CN(C)c1cccc(Nc2ncc3ccc(-c4cccc(Cl)c4)n3n2)c1
Temperature: 180 °C
Yield: 3.9 %

Procedure:
7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (76.2 mg, 0.000261 mol), N,N-Diisopropylethylamine (0.0682 mL, 0.000392 mol) and N,N-Dimethyl-benzene-1,3-diamine (71.1 mg, 0.000522 mol) were dissolved in 2-Methoxyethanol (1.83 mL, 0.0232 mol) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 3.73 mg of N-[7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N′,N′-dimethyl-benzene-1,3-diamine as a lyophilated powder. (M+H)=364.11. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.37 (d, 1H, J=9.60 Hz), 8.10 (s, 1H), 7.89 (d, 1H, J=7.58 Hz), 7.44 (m, 3H), 7.20 (d, 1H, J=4.80 Hz), 7.03 (d, 1H, J=4.54 Hz), 6.61 (m, 2H), 3.11 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:36][CH2:37][O:38][CH3:39])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([O:31]CC)=[O:30])[NH:26]4)=[CH:22][C:21]=3[O:34][CH3:35])=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:36][CH2:37][O:38][CH3:39])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([OH:31])=[O:30])[NH:26]4)=[CH:22][C:21]=3[O:34][CH3:35])=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(OC)c(NC(=O)C(CCOC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: COCCC(C(=O)Nc1cc2[nH]c(C(=O)O)cc2cc1OC)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
80 mg (135 μmol) of ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-5-methoxy-1H-indole-2-carboxylate (racemate) were hydrolysed with lithium hydroxide at RT according to General Method 3. Yield: 63 mg (purity 90%, 74% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16].OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:16][C:15](=[O:17])[CH2:14][CH2:13][C:12]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])=[O:18]
Reactant: COc1cc(C)c(C(=O)CCC(=O)O)c(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1c(C)cc(OC)cc1OC
Temperature: 75 °C

Procedure:
A mixture of 4-(2,4-dimethoxy-6-methyl-phenyl)-4-oxo-butyric acid (3.70 g, 14.68 mmol) and concentrated H2SO4 (0.2 mL) in MeOH (50 mL) was heated at 75° C. for 1 hour and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 4-(2,4-dimethoxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (3.86 g, quant.). 1H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.50 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 3.10 (t, J=8.1 Hz, 2H), 2.65 (t, J=8.1 Hz, 2H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)=[O:25]
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)C1CCN(c2ncc(N)cc2C)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cnc(N2CCC(C(=O)OC)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To an ice-water cooled solution of methyl 1-(5-amino-3-methylpyridin-2-yl)piperidine-4-carboxylate (2.14 g; 8.59 mmol) in DCM (43 mL) was added methyl chloro(oxo)acetate (1.03 mL; 11.17 mmol) followed by pyridine (834 μL; 10.31 mmol) and the reaction mixture was allowed to stir at ˜0° C. for 30 mins, then allowed to warm to room temperature. The reaction solution was washed with water (40 mL) then saturated brine (40 mL). The organics were dried over MgSO4, filtered and evaporated under vacuum to yield a pale tan solid (2.01 g, 70% yield). This was used for the next stage without further purification. 1H NMR δ 1.60-1.80 (m, 2H), 1.85-1.99 (m, 2H), 2.18 (s, 3H), 2.54-2.62 (m, 1H), 2.69-2.88 (m, 2H), 3.26-3.40 (m, 2H), 3.56 (s, 3H), 3.82 (s, 3H), 7.87 (d, 1H), 8.40 (d, 1H), 10.75 (s, 1H). MS m/e MH+ 336.20.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: CS(=O)(=O)c1ccc(F)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(S(C)(=O)=O)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-fluoro-4-methylsulfonyl-benzene following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>CO.CN1CCOCC1>[C:15]([CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:8])=[CH:19][CH:18]=1)([OH:17])=[O:16]
Reactant: COc1ccc(C(=O)c2ccc(OCC(=O)O)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Product: COc1ccc(C(O)c2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.2 g of 4-(4-methoxybenzoyl)phenoxyacetic acid are dissolved in 600 ml of 80% strength methanol (reflux), and 4.4 ml of N-methylmorpholine are added. 6 g of sodium borohydride are added in portions over the course of two hours, and the reaction is continued under reflux conditions for 3 hours. The mixture is cooled to room temperature and acidified to pH 2.5 with 3N HCl. The methanol is distilled off, the aqueous phase is extracted with ethyl acetate, and the organic phase is washed with brine and dried over sodium sulfate. After removal of the ethyl acetate by distillation there remains a white amorphous powder. The product is used directly for the next reaction.
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>C(O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][N:30]=[C:17]2[CH2:18][CH2:19][CH:14]([NH:13][C@H:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=3)[CH2:15][CH2:16]2)=[CH:25][CH:24]=1
Reactant: NNc1ccc(Br)cc1
Reactant: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1CCC(=O)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1CCC(=NNc2ccc(Br)cc2)CC1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
To a solution of 22.3 gm (85.01 mMol) N-((R)-(+)-α-methyl-(4-nitrophenyl)ethyl)-4-aminocyclohexanone in 375 mL ethanol were added 19.0 gm (85.0 mMol) 4-bromophenylhydrazine hydrochloride and 6.73 gm (85.1 mMol) pyridine. The reaction mixture was heated to 80° C. for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic solution was washed sequentially with aqueous potassium carbonate and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 31.66 gm (86%) N-((R)-(+)-α-methyl-(4-nitrophenyl)-ethyl)-4-aminocyclohexanone 4-bromophenylhydrazone as a brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[F:23][CH:24]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C@@H:24]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:25][N:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1
Reactant: O=S(=O)(c1ccc(O)cc1)[C@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)CCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)[C@H]1CCN(C[C@@H](F)CCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=378.3 (M+H+) was prepared from (S)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and (RS)-toluene-4-sulfonic acid 2-fluoro-4-phenyl-butyl ester.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:20][C@H:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].Cl.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
Z-Tle (15.6 g, 59.1 mmol), Leu-OEt HCl (11.56 g, 59.1 mmol), and N-methyl morpholine (NMM) (12.75 mL) are mixed with 45 mL of DMF and a cloudy suspension forms. The mixture is cooled to 0° C. and treated with TBTU (19.1 g, 59.48 mmol), then stirred at 0° C. for 15 minutes, then removed from the cold bath and stirred for 1.5 hours. The mixture is poured into 500 mL of a saturated solution of sodium carbonate which is then extracted with two 350 mL portions of ethyl acetate. The combined organic extracts are washed with 500 mL of 1 M KHSO4 water and brine and then dried over sodium sulfate. The solvents are removed to give Z-Tle-Leu-OEt (24.1 g). FABMS M+1 407
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[CH:26]=[CH:25][C:23](N)=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[C:22]([F:27])[CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(Br)cc1F
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Br)cc4F)c3c2s1
Yield: 30 %

Procedure:
Prepared from VII and 4-bromo-2-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 30%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3325, 3053, 2230, 1649, 1614, 1582, 1556, 1499, 1462, 1380, 1351, 1250, 1154, 1132, 1052, 969, 904, 875, 817; 19F NMR (282 MHz, DMSO-d6) δ −119.9; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=9.0 Hz), 8.26 (d, 1H, J=9.0 Hz), 7.78 (m, 1H), 7.55-7.52 (m, 1H), 7.38-7.25 (m, 2H); HRMS calcd for C16H8N5SBrF (M+H+): 399.9668, found 399.9662.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=1)#[N:2].[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:20][C:19]1[C:14]([NH:13][C:7]2[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:22])=[N:15][C:16]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=3[CH:25]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: Cc1cccc(C(=O)NCC#N)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: Cc1cccc(C(=O)NCC#N)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 12.4 %

Procedure:
N-Cyanomethyl-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-benzamide (50.0 mg, 0.000149 mol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (30.4 mg, 0.000149 mol) and 10-Camphorsulfonic acid (34.6 mg, 0.000149 mol) were suspended in Isopropyl alcohol (3.0 mL, 0.039 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The reaction mixture was then reduced under nitrogen and the crude residue was isolated and purified by Gilson prep HPLC to afford 9.33 mg (12%) of 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-cyanomethyl-3-methyl-benzamide. LC/MS (ESI): 504.15. 1H NMR (400 MHz, DMSO, d6) δ 9.15 (s, 1H), 9.08 (m 1H), 8.93 (m, 1H), 8.80 (m, 1H), 8.11 (s, 1H), 7.50 (m, 2H), 7.34 (m, 3H), 6.61 (d, 1H, J=8.59 Hz), 4.21 (d, 2H, J=5.05 Hz), 2.32 (s, 3H), 2.12 (m, 2H), 1.93 (m, 2H), 1.22 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](ON2C(=O)CCC2=O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]2)=[O:28])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
N-Benzylpiperazine (40.0 ml) was added in one portion to a solution of succinimido 1-t-butoxycarbonylpiperidine-4-carboxylate (75.0 g) in dry dichloromethane (1600 ml). The solution was stirred at ambient temperature under an atmosphere of argon for 17 hours. The solution was washed with water (500 ml) and saturated brine (250 ml). The organic layer was dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on alumina, eluting with dichloromethane to give 1-benzyl-4-[(1-t-butoxycarbonyl-4-piperidyl)carbonyl]piperazine as an oil;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-n2c(C)ccc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 60.6 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (400 mg, 1.57 mmol), p-amino-acetophenone (234 mg, 1.73 mmol) and p-toluenesulfonic acid (30 mg) in toluene (40 ml) was heated to reflux for 5 hours. The reaction mixture was cooled, filtered and concentrated. The crude reddish solid (1.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-[4-[2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-1-yl]phenyl]ethanone (336 mg, 61%) as a white solid: mp 179-80° C. Anal Calc'd. for C20H19NSO3 ·0.1 H2O: C, 64.67; H, 5.70; N, 3.77; S, 8.63. Found: C, 64.68; H, 5.52; N, 3.82; S, 8.08.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.[OH-].[Li+]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][C:3]([OH:32])=[O:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester (Example 57) (342 mg, 0.78 mmol) in THF (5 mL) at room temperature was treated with an aqueous solution (1 mL) containing lithium hydroxide monohydrate (36 mg, 0.858 mmol). The reaction mixture was allowed to stir for 2 h and then evaporated to a small volume. The reaction mixture was then dissolved in water (5 mL) and the pH adjusted to ˜7 with 1 N HCl to precipitate product. The precipitate was then triturated with water (2×5 mL) and dried under a stream of nitrogen to afford product as a colorless solid (318 mg, 96%). 1H NMR (CDCl3) 1.43-1.57 (m, 2H), 1.77-1.79 (m, 6H), 3.02-3.15 (m, 2H), 3.27 (br s, 2H), 3.51 (br s, 1H), 3.74 (s, 3H), 3.77-3.89 (m, 2H), 4.57-4.59 (m, 1H), 6.24-6.31 (m, 2H), 6.55 (br s, OH), 6.67 (d, J=8.6, 1H) 7.18-7.27 (m, 5H). LC/MS 5.34 min, [M+1]+ 425.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13]O)([O-:3])=[O:2].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1NCCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1NCCCCl
Reaction time: 6 h
Yield: 100 %

Procedure:
To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)amino-1-propanol and 225 parts of trichloromethane are added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: the temperature rises to 45° C.). Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 43 parts (100%) of N-(3-chloropropyl)-2-nitrobenzenamine as a residue.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH3:14]
Reactant: CCCC1(C(=O)OCC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 109.7 %

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.67 ml) was slowly added, then benzoyl chloride (5.33 ml, 0.045 mol) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.00 g of yellow liquid, MS: m/e 305(M+″+1), 304(M+), 259, 230, 199, 182, 153, 105(base), 77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][OH:15])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[OH:15][CH2:14][CH2:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COc1cc2c(cc1OCCO)C(=O)CC2
Product: COc1cc2c(cc1OCCO)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 68 %

Procedure:
Using the procedure of Example 1, 5-methoxy-6-(2-hydroxyethoxy)indan-1-one (222 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7-(2-hydroxyethoxy)-8-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (239 mg, 68% of theory).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:28])(=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1>CS(C)=O>[NH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:28])(=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:3]([NH2:5])=[NH:2]
Reactant: N=C(N)N
Reactant: O=S(=O)(Nc1ccccc1)c1ccc2ccnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N=C(N)Nc1nccc2ccc(S(=O)(=O)Nc3ccccc3)cc12
Temperature: 60 °C
Yield: 13.6 %

Procedure:
Guanidine hydrochloride (100 mg, 1.05 mmol) was added in one portion to a suspension of sodium hydride (NaH) (30 mg, 80% dispersion by wt. in mineral oil, 1.0 mmol) in dimethylsulphoxide (DMSO) (3.5 mL) and the mixture was heated at 60° C. under nitrogen (N2) for 30 minutes. 1-Chloro-7-phenylsulphamoylisoquinoline (110 mg, 0.345 mmol) was added and the mixture was heated at 100° C. for 3 d. The solvents were evaporated in vacuo and the residue was purified by column chromatography (silica gel using CH2Cl2-methanol-0.880NH3 (97:3:0.3 to 90:10:1) as eluant) to give 1-guanidino-7-phenylsulphamoylisoquinoline (16 mg, 0.047 mmol) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9]Br>N1C=CC=CC=1>[Br:9][C:6]1[C:5]([OH:8])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrBr
Solvent: c1ccncc1
Product: Cc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 6-methyl-pyridin-3-ol (5.0 g, 45.82 mmol) in pyridine (15 mL) was added bromine (3.66 g, 22.91 mmol). The reaction was stirred at room temperature under N2 for 20 h. The crude reaction mixture was poured on to crushed ice-water (300 mL) and stirred for 3 h. The reaction was extracted with ethyl acetate (5×100 mL), washed with brine, dried with Na2SO4, filtered, and concentrated to afford 6.3 g (738%) of I-115 as light yellow solid.
Reaction SMILES: [N:1]([CH:4]1[CH:9]([OH:10])[CH2:8][CH2:7][CH:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-]>[Pd].C(OCC)(=O)C>[NH2:1][CH:4]1[CH:9]([OH:10])[CH2:8][CH2:7][CH:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1
Reactant: CCOC(=O)C1CCC(O)C(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O)C(N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A suspension mixture of Racemate-ethyl 3-azido-4-hydroxycyclohexanecarboxylate (8.0 g, 37.5 mmol) and 5% palladium on carbon (50% wet, 2.0 g) in ethyl acetate (250 mL) was stirred under hydrogen atmosphere (˜1 atm) at room temperature overnight. After the reaction mixture was filtered, the filtrate was concentrated to thereby give the title compound (5.8 g, 83%) as a yellow solid. MS (ES+) C9H17NO3 requires: 187, found: 188 [M+H]+.