Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][C:33]1([F:36])[F:35].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH:32]4[CH2:34][C:33]4([F:36])[F:35])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: FC1(F)CC1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5CC5(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (40 mg, 0.096 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (32.8 mg, 0.19 mmol) and triethylamine (20.2 μL, 0.14 mmol) in 1 mL of DMF was heated at 150° C. in a microwave reactor for 30 min. The crude product was purified by RP-HPLC to afford 5-chloro-N2-(4-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; ESMS m/z 506.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[CH:15]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:22]([NH2:23])=[N:21][CH:20]=[N:19][C:18]=3[N:14]([CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:15]=2)=[CH:29][CH:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of (S)-2-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.03 mmol) in 10 ml of DCM, TFA (10 ml) was added. The reaction mixture was stirred at RT for 2 h. The mixture was concentrated to give (S)-5-(4-phenoxyphenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (400 mg), which was subjected to the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:12]3[CH:11]=[CH:15][N:14]=[CH:13]3)=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12

Procedure:
9.54 g (30 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid and 6.32 g (39 mmol) of N,N'-carbonyldiimidazole in 50 ml of dry dimethylformamide are stirred at room temperature for 1 hour and at 50° for 1 hour. Subsequently, the mixture is poured into about 300 ml of water, the precipitated material is filtered off under suction, washed with water and dried to constant weight. There is obtained (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole of melting point 240°-241.5°.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([C:32](O)=[O:33])[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18]>>[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:32]([C:22]3[CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:33])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: CN(C)c1ccc(N2CCNCC2)cc1
Product: CN(C)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)cc1

Procedure:
The tide compound was prepared according to the procedure E described for Example 9 from Dimethyl-(4-piperazin-1-yl-phenyl)-amine [91703-23-0] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 464.3 MH+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CS(O)(=O)=O>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: CS(=O)(=O)O
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCn1ncc2c(NCc3ccccn3)c3ccccc3nc21
Temperature: 110 °C
Yield: 76.7 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 2-aminomethylpyridine (0.9 mL, 0.0086 mol) was heated at 110° C. overnight. The reaction mixture was cooled and then was poured into water. The mixture was extracted with CH2 Cl2 and then the CH2Cl2 layer was evaporated. The residue was purified by column chromatography on silica gel eluting with 20% hexane/ethyl acetate to afford the product as the free base. The free base was then dissolved in methanol and was treated with methanesulfonic acid. The methanol was evaporated and the residue was recrystallized from 2-propanol/ether and dried in vacuo to afford 1.0 g of 1-ethyl-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.2CH3SO3H, as a yellow solid m.p. 259°-260° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:22]=[C:21]([CH2:20][CH2:19][C:18]([NH:17][CH2:16][CH2:15][NH:14][CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6](=[O:13])[NH:5][N:4]=3)=[O:34])[O:25][N:24]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2noc(CCC(=O)NCCN)n2)cc1
Reactant: O=c1[nH]nc(CCl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2noc(CCC(=O)NCCNCc3n[nH]c(=O)c4ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2H-phthalazin-1-one (9.7 mg, 0.05 mmol) in DMF (200 μL), N-(2-amino-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide (14.4 mg, 0.05 mmol) and DIPEA (9 μL, 0.05 mmol) were added. The mixture was stirred overnight at rt and directly applied to preparative HPLC. The purity was determined by RPLC/MS.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:30][CH:31]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc(-n2cccc2)cc1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-(1-pyrrolyl)benzoic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-(1-pyrrolyl)benzamide as an off white powder, m.p. 173.0-174.9° C. 1H NMR (300 MHz, DMSO-d6) δ8.52 (t, J=5.5 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.48 (t, J=2.2 Hz, 2H), 7.39 (m, 1H), 7.19 (dt, J=7.6, 1.1 Hz, 1H), 6.53 (broad s, 2H), 6.30 (t, J=2.2 Hz, 2H), 4.57 (t, J=7.0 Hz, 2H), 3.82 (t, J=6.7 Hz, 2H), 3.33 (m, 2H), 3.26 (s, 3H), 3.20 (t, J=6.7 Hz, 2H), 1.87 (m, 2H), 1.71 (m, 2H); MS (EI) m/e 482.2421 (482.2430 calcd for C28H30N6O2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:14].B([C:18]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])(O)O>C1COCC1>[Cl:30][C:28]1[CH:29]=[CH:18][C:19]([O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])=[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:14])[CH:27]=1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)c(F)c1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(=O)(=O)N(C)C)cc1F)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (i), the product from example 151 step (iv) and THF as solvent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](Cl)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
24.4 g of 4-hydroxybenzaldehyde is mixed with 50 ml of dimethylformamide, 30.4 g of cinnamyl chloride and 30.4 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 100°-110° C. for 5 hours and then cooled. The cooled mixture is added to 2 l of ice water to deposit solid. The solid is separated therefrom by filtration and then washed with water until the solid becomes neutral. The washed solid is dried and then recrystallized from 200 ml of ethanol to obtain 36.4 g of 4-cinnamyloxybenzaldehyde. Thus obtained 4-cinnamyloxybenzaldehyde has a melting point of 89.5°-90.5° C.
Reaction SMILES: Cl.N1([C:14](=[O:15])[C:13]2[N:11](C)C=N[C:8]=2N(C)C1=O)C.[CH:16]1(C)[CH2:21][CH2:20][CH:19](C(C)C)[CH:18]([OH:25])[CH2:17]1>O>[CH:18]([O:25][C:14](=[O:15])[C@H:13]([CH2:8][C:21]1[CH:16]=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=1)[NH2:11])([CH3:19])[CH3:17]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (120 g) was dissolved in water (1 L). Caffeine (100 g) and menthol (20 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[NH:11][S:10]2(=[O:19])=[O:18])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[NH:11][S:10]1(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C1NS(=O)(=O)N(CSc2ccccc2)C1=O
Solvent: ClCCl
Product: CC(C)C1NS(=O)(=O)N(CCl)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a solution of 2-phenylthiomethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3.8 g) in 60 ml of methylene chloride was added sulfuryl chloride (1.52 ml) and the mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (200 ml) for 2 hours, and the resulting solid filtered and dried to afford 2.7 g (94%) of 2-chloromethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =isopropyl; R3 =H; X'=Cl) as a solid, m.p. 71°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5](=[N:7][OH:8])[NH2:6].[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[NH:23][C:24]1[NH:28][C:27]2[C:29]3[CH2:30][C:31]([CH3:41])([CH3:40])[O:32][C:33]=3[C:34]([C:36](OC)=O)=[CH:35][C:26]=2[N:25]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:36]([C:34]3[C:33]4[O:32][C:31]([CH3:41])([CH3:40])[CH2:30][C:29]=4[C:27]4[NH:28][C:24]([NH:23][C:17]5[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=5[Cl:15])=[N:25][C:26]=4[CH:35]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: NC(=NO)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(-c3nc(-c4ccc(F)c(Cl)c4)no3)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 20.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-156 using 3-chloro-4-fluoro-N′-hydroxybenzimidamide (Intermediate-53, 0.072 g, 0.30 mmol), sodium hydride (0.021 g, 0.51 mmol), methyl 2-((2-chloro-6-chlorophenyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-1 of Intermediate-6, 0.100 g, 0.255 mmol) and THF (5.0 mL) to afford 0.029 g of the desired product. 1HNMR (DMSO-d6): δ 1.33 (s, 6H), 3.08 (s, 2H), 7.26 (bs, 1H), 7.55 (m, 3H), 7.65 (t, J=8.7 Hz, 1H), 8.06 (s, 1H), 8.06 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 11 (bs, 2H); MS [M+H]+: 544.17.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[C:34]2[CH2:33][CH2:32][CH:31]([CH2:35][C:36]3[N:37]=[CH:38][NH:39][C:40]=3[CH3:41])[C:30](=[O:42])[C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2.C(N(CC)CC)C.O>CN(C=O)C>[CH3:21][N:22]1[C:34]2[CH2:33][CH2:32][CH:31]([CH2:35][C:36]3[N:37]=[CH:38][N:39]([C:7]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:40]=3[CH3:41])[C:30](=[O:42])[C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 57 %

Procedure:
A solution of triphenylchloromethane (286 mg) in dry DMF (10 ml) was added dropwise to a stirred solution of 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one (292 mg) and triethylamine (101 mg) in dry DMF (20 ml) and the resulting solution was stirred at room temperature under nitrogen for 3.5 h. The reaction mixture was then poured into water (100 ml) and the resultant suspension was extracted with dichloromethane (3×50 ml). The combined, dried organic extracts were adsorbed onto FCC silica which was then applied to a column and FCC eluting with System A (150:8:1) gave a solid which was further purified by crystallisation from dichloromethane:hexane (2:1) to give the title compound (304 mg), m.p. 193°-195°.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[C:45](O)(=[O:49])[CH:46]([CH3:48])[CH3:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CC(C)C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and isobutyric acid (34 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water and dried to give 1-((1R,5S)-8-{2-[4-(1,3-benzodioxol-5-yl)-1-isobutyrylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a solid (0.15 g, 72%). HRMS C33H42N4O3 m/z 543.3335 (M+H)Cal. 543.3322 (M+H)Obs..
Reaction SMILES: [Na].[C:2]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:31])[CH:21]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:18]
Reactant: Oc1ccc(C2=CCCCCCC2)cc1
Reactant: CCCCCCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 2.1 g of sodium in 100 ml of absolute ethanol are added stirring 15 g of p-(1-cyclooctenyl)-phenol. After stirring has continued for a further 30 minutes, 31.5 g of 2-bromo-decanoic acid ethyl ester are slowly added dropwise to this solution and the mixture is maintained at 50° C for 24 hours. After the solvent has been removed in vacuo, the residue is partitioned at 0° C between ether and 2N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and evaporated in vacuo, to thus yield the oily α-[p-(1-cyclooctenyl)-phenoxy]-decanoic acid ethyl ester of the formula ##STR11##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25])([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.048 mMol 3-nitrobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:30])[S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([O:20]CC[Si](C)(C)C)=[O:19])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:30])[S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([OH:20])=[O:19])(=[O:13])=[O:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N(C)S(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C)S(=O)(=O)c2cccc(C(=O)O)c2)cc1
Yield: 95.2 %

Procedure:
A mixture of 1.5 g of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl](methyl)sulfamoyl}benzoate, a solution of TBAF in THF (1.0 M, 7.0 mL), and 15 mL of THF was stirred at room temperature for 2 hours. To the reaction mixture was added 0.2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2 M hydrochloric acid, water, and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.11 g of 3-{[4-(methoxycarbonyl)phenyl](methyl)sulfamoyl}benzoic acid as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9]>[OH-].[Na+].O1CCOCC1>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:9])=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To β-alanine (1.14 g) in 4N sodium hydroxide (7.8 ml) was added p-nitrobenzyl chloroformate (3 g) in dioxane (8 ml) with ice-cooling and stirred for 1 hour. The reaction mixture was filtered and the filtrate was neutralized with hydrochloric acid. The resulting precipitate was collected to give N-p-nitrobenzyloxycarbonyl-β-alanine, which was then converted into the corresponding acid chloride by reaction with thionyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCCN(C)C)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (0.85 g, 3.7 mmol) in THF (40 mL), triphenyl phosphine (2.91 g, 11.1 mmol) and 2-dimethylamino ethanol (1.11 mL, 11.1 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (2.15 mL, 11.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to a purification on preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times to afford N-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide as a colorless waxy solid in 51.2% yield. LCMS m/z (%)=303 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 7.63 (d, J=8.93 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.14 (d, J=8.98 Hz, 1H), 6.25 (s, 1H), 4.07 (t, J=5.82 Hz, 2H), 3.69 (s, 3H), 2.56 (t, J=5.80 Hz, 2H), 2.15 (s, 6H), 2.05 (s, 3H).