Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:16]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:15]3)=[CH:11][CH:10]=2)[N:6]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:16]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:15]3)=[CH:32][CH:33]=2)[N:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(C)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(COc2ccc(Cn3cc(CCC(=O)O)c(-c4ccccc4)c3)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-methyl-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (368 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 4 hours, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(2-methyl-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (251 mg, yield: 73%). This was recrystallized from ethanol-hexane. Melting point: 113–114° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[C:14]([CH:22]([CH3:26])[C:23](O)=[O:24])=[CH:13][C:12]2=[O:27])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[C:14]([CH:22]([CH3:26])[C:23]([Cl:3])=[O:24])=[CH:13][C:12]2=[O:27])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)O)c3cc(C)ccc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)Cl)c3cc(C)ccc32)cc1

Procedure:
Thionyl chloride (0.109 ml.) was added by syringe to a suspension of α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionic acid (0.335 g.) in toluene (3.5 ml.) (dried over sodium wire). The mixture was heated under reflux until evolution of gas ceased, and was then evaporated in vacuo. The residue was mixed with further dry toluene (5 ml.) and then evaporated in vacuo, and dried at ambient temperature under high vacuum, to give α-[1(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionyl chloride, which was dissolved without purification in dry toluene (2.5 ml.). The solution thus obtained was added by syringe to a solution of phenol (0.052 g.) in pyridine (0.044 ml.). The mixture was then stirred at ambient temperature for 45 minutes and then at 80° C. for 30 minutes. After being left at ambient temperature overnight, the reaction solution was mixed with ethyl acetate (20 ml.). The solution was then washed successively with 2N-hydrochloric acid (20 ml.), water (20 ml.), 2N-sodium hydroxide solution (2 × 20 ml.), water (20 ml.) and then saturated sodium chloride solution (20 ml.). The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was recrystallised from cyclohexane to give phenyl α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionate, m.p. 111°-113° C., in 58% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[C:15]3[N:20]([CH:21]=2)[N:19]=[C:18]([NH:22][C:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][C:33](O)=[O:34])[CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:17]=[CH:16]3)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:4].[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[C:15]3[N:20]([CH:21]=2)[N:19]=[C:18]([NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[CH:32][C:33](=[O:34])[NH:45][O:44][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][O:38]4)[CH:26]=2)[CH:17]=[CH:16]3)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:4]
Reactant: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(C=CC(=O)O)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: NOC1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(C=CC(=O)NOC5CCCCO5)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 20-mL vial is charged with acetonitrile (0.4 mL), 3-[3-[[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]carbamoyl]phenyl]prop-2-enoic acid (0.025 g, 0.05 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.0088 g, 0.08 mmol), triethylamine (0.021 mL, 0.15 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.033 g, 0.08 mmol). The mixture is stirred at room temperature for 2 hr, concentrated and taken up into saturated aqueous Na2CO3 (2 mL), extracted with EtOAc and CH2Cl2. Organic layers are combined, dried and concentrated to give crude N-[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]-3-[3-oxo-3-(tetrahydropyran-2-yloxyamino)prop-1-enyl]benzamide. This is taken up in a mixture of aqueous HCl (1 mL, 1M) and MeOH (1 mL), and is stirred at 50° C. for 1 hour. The mixture is concentrated, taken up in DMSO (1 mL) and purified on a Gilson preparative HPLC (reverse phase) to afford the title compound (0.015 g). LCMS (m/z)=513.5 [M+H]+, tR=2.31 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O.[F-].[Cs+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:25]=1)=[O:35])=[C:14]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[F:44])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OCc3ccccc3)ccc12
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccccc2F)ccc2cc(OCc3ccccc3)ccc12
Yield: 60.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.00 g, 1.63 mmoles) in 20 ml of acetonitrile and add 2-fluorobenzene boronic acid (0.46 g, 3.26 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.23 gm., 0.33 mmoles) and sonicate briefly. Next add cesium fluoride (2.23 g, 14.67 mmol) and heat to 75° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Further purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to isolate 550 mg of the title compound (60%).
Reaction SMILES: [N:1]1[N:8]2[C:4]([O:5][C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=32)=[CH:3][C:2]=1[CH2:13][OH:14]>C(Cl)(Cl)Cl.O=[Mn]=O>[N:1]1[N:8]2[C:4]([O:5][C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=32)=[CH:3][C:2]=1[CH:13]=[O:14]
Reactant: OCc1cc2oc3c(n2n1)CCOC3
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2oc3c(n2n1)CCOC3
Yield: 80.6 %

Procedure:
To the stirred solution of 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethanol (1.0 g, 5.1 mmol) in 60 ml of CHCl3 was added 8 g of MnO2. Th suspension was refluxed for 1.5 hour under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give yellow oil. The product was purified by chromatography. 0.79 g of the product was obtained (80%); (M+H) 193
Reaction SMILES: C([O:8][CH:9]1[CH2:12][CH:11]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]([O:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][CH3:31])=[O:29])[C@@H:23]([CH3:32])[CH2:22][CH2:21]4)[CH:15]=[N:14]2)[CH2:10]1)C1C=CC=CC=1>[Pd].CO>[CH:34]1([O:33][C:19]2[C:18]([C:16]3[CH:15]=[N:14][N:13]([CH:11]4[CH2:12][CH:9]([OH:8])[CH2:10]4)[CH:17]=3)=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][C@H:23]([CH3:32])[N:24]3[C:28]([O:30][CH3:31])=[O:29])[CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC(OCc5ccccc5)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1c2ccc(-c3cnn(C4CC(O)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium on carbon (10 wt %, 0.060 g) was added to a solution of (S)-methyl 6-(1-(3-(benzyloxy)cyclobutyl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.060 g, 0.12 mmol) in methanol (10 mL), and the resulting mixture stirred at room temperature under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge Prep Shield RP18 OBD Column, 19×150 mm, 5 um; mobile phase, Water (0.05% ammonium bicarbonate) and acetonitrile (30% to 50% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV254&220 nm. This afforded (S)-methyl 5-cyclobutoxy-6-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.031 g, 63%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.16 (d, J=6.30 Hz, 3H), 1.32-1.51 (m, 2H), 1.55-1.68 (m, 1H), 2.00-2.33 (m, 5H), 2.33-2.58 (m, 3H), 2.76-2.84 (m, 2H), 2.93-3.01 (m, 1H), 3.77 (s, 3H), 4.12-4.19 (m, 1H), 4.51-4.64 (m, 2H), 4.99-5.08 (m, 1H), 7.24-7.35 (m, 2H), 7.86 (s, 1H), 8.04 (s, 1H). MS (ESI, pos. ion) m/z 412 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:13][C@H:9]1[C@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:11][C:10]1=[O:12]
Reactant: O=C1N[C@@H](Sc2ccccc2)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H]1C(=O)N[C@H]1Sc1ccccc1

Procedure:
To a solution of 2.65 g of (3R,4S)-4-phenylthio-3-tritylamino-2-oxoazetidine in 20 ml of acetone is added under ice-cooling 1.27 g of p-toluenesulfonic acid monohydrate, followed by similar procedure to Reference Example 45B to give 1.9 g of tosyl salt of (3R,4S)-3-amino-4-phenylthio-2-oxoazetidine.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:24])[NH:16][C:17]2[C:21]([C:22]=1Cl)=[CH:20][S:19][CH:18]=2)=[O:13])[CH3:10].[N:25]1([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:24])[NH:16][C:17]2[C:21]([C:22]=1[N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[O:32])[CH2:26][CH2:27]1)=[CH:20][S:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(Cl)c2cscc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Temperature: 110 °C
Yield: 89.9 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (2.07 g, 10.16 mmol) was added to a solution of 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (39) (2.4 g, 9.24 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (1.99 g, 10.16 mmol) in dry DMA. The solution was heated at 110° C. for 3 h. The solution was cooled and the solvent was distilled. The residue was suspended in water, sonicated briefly, and filtered. The solids were washed by excess water and dried to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (3.47 g, 90%) as white solids. MP 282° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 3.27 (m, 4H), 3.77 (m, 4H), 4.24 (q, J=7.2 Hz, 2H), 6.86 (d, J=3.6 Hz, 1H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.46 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.02 (d, J=3.2 Hz, 1H), 11.30 (s, 1H) ppm; MS m/z=418 amu (M++1).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([O:18]C(=O)C)[CH2:13][O:14]C(=O)C)=[O:9])=[C:6]([I:22])[C:5]([C:23]([NH:25][CH2:26][CH:27]([O:33]C(=O)C)[CH2:28][O:29]C(=O)C)=[O:24])=[C:4]([I:37])[C:3]=1[NH:38][C:39]([NH:41][C:42]1[C:47]([I:48])=[C:46]([C:49]([NH:51][CH2:52][CH:53]([O:59]C(=O)C)[CH2:54][O:55]C(=O)C)=[O:50])[C:45]([I:63])=[C:44]([C:64]([NH:66][CH2:67][CH:68]([O:74]C(=O)C)[CH2:69][O:70]C(=O)C)=[O:65])[C:43]=1[I:78])=[O:40].[OH-].[Na+]>O.CO>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:18])[CH2:13][OH:14])=[O:9])=[C:6]([I:22])[C:5]([C:23]([NH:25][CH2:26][CH:27]([OH:33])[CH2:28][OH:29])=[O:24])=[C:4]([I:37])[C:3]=1[NH:38][C:39]([NH:41][C:42]1[C:47]([I:48])=[C:46]([C:49]([NH:51][CH2:52][CH:53]([OH:59])[CH2:54][OH:55])=[O:50])[C:45]([I:63])=[C:44]([C:64]([NH:66][CH2:67][CH:68]([OH:74])[CH2:69][OH:70])=[O:65])[C:43]=1[I:78])=[O:40]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)Nc2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 40 °C
Reaction time: 6 h

Procedure:
N,N'-bis[2,4,6-triiodo-3,5-bis(2,3-diacetoxypropylaminocarbonyl)phenyl]-urea (4.0 g, 2.26 mmol) was dissolved in a 1:1 mixture of water and methanol (25 ml) containing NaOH (1.44 g, 36 mmol). After stirring for 6 h at 40° C., the solution was treated with a strongly acidic ion exchange resin (Amberlyst 15), the solvent was separated and evaporated to give pure product. Yield: 3.24 g (100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](O)[CH:22]=[C:21]3[C:16]=2[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]4[O:34][CH2:35][O:36][C:28]=24)=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC(S([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:33][C:32]1[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:24][C:15]=3[O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:20]=[CH:19][N:18]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 95 °C
Yield: 42.1 %

Procedure:
A mixture of 5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazoline (0.15 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.089 g), potassium carbonate (0.1 g) and DMF (3 ml) was stirred and heated to 95° C. for 24 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was washed with 1N aqueous sodium hydroxide solution and with brine and dried over magnesium sulphate. The organic solution was filtered and a 6N solution of hydrogen chloride in diethyl ether (2 ml) was added. The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated. The residue was dissolved in methylene chloride (3 ml) and a saturated methanolic ammonia solution (1 ml) was added. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.061 g); NMR Spectrum: (CDCl3) 1.85–2.0 (m, 2H), 2.3 (m, 2H), 2.8–2.95 (m, 2H), 3.1–3.3 (m, 2H), 4.5 (m, 2H), 4.72 (m, 1H), 6.08 (s, 2H), 6.6 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 7.0 (d, 1H), 8.58 (s, 1H), 9.32 (s, 1H); Mass Spectrum: M+H+ 497 and 499.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C=O.[CH:33](O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH3:33])[CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CCNCC2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2ccc(C(=O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone (0.3 g, 0.70 mmol) obtained in Example 15, formaldehyde (0.086 ml, 1.06 mmol) and formic acid (0.9 ml) was heated at 100° C. for 4 hours, then poured into water, made basic with 8 N aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the residues were purified by alumina column chromatography (developing solvent; ethyl acetate-methanol=10:1), whereby 0.15 g of the title compound was obtained as colorless powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:47]1([C:53]2[N:54]=[C:55]([NH2:58])[NH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:47]1([C:53]2[N:54]=[C:55]([NH:58][C:20]([C:19]3[C:13]4[N:12]=[C:11]([C:3]5[N:2]=[CH:1][C:10]6[C:5]([CH:4]=5)=[CH:6][CH:7]=[CH:8][CH:9]=6)[NH:15][C:14]=4[CH:16]=[CH:17][CH:18]=3)=[O:21])[NH:56][CH:57]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Nc1nc(-c2ccccc2)c[nH]1
Reactant: O=C(O)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1nc(-c2ccccc2)c[nH]1)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Yield: 17.4 %

Procedure:
120 mg (0.4 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid was reacted with 400 mg (1.1 mmol) of HBTU and 160 mg (1.0 mmol) of 4-phenyl-1H-imidazol-2-ylamine (160 mg, 1 mmol) according to the general procedure A. The residue was purified by flash column chromatography (EtOAc) to provide 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (4-phenyl-1H-imidazol-2-yl)-amide (30 mg, 17.5%). LCMS: 431 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(NC3CCOCC3)nc2)o1
Yield: 49 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) was converted using 4-aminotetrahydropyran instead of morpholine to the title compound (117 mg, 49%) which was obtained as a light yellow solid. MS: m/e=404.4 [M+H]+.
Reaction SMILES: [C:1]([C@H:5]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49](=[O:66])[NH:50][C@:51]2([C:56](=[O:65])[NH:57][S:58]([C:61]3([CH3:64])[CH2:63][CH2:62]3)(=[O:60])=[O:59])[CH2:53][C@H:52]2[CH:54]=[CH2:55])[O:41][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][C@@H:28]3[O:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:67][C@H:9]2[O:8][C:7](=[O:68])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C@H:5]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49]([NH:50][C@:51]2([C:56](=[O:65])[NH:57][S:58]([C:61]3([CH3:64])[CH2:62][CH2:63]3)(=[O:59])=[O:60])[CH2:53][C@H:52]2[CH:54]=[CH2:55])=[O:66])[O:41][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][C@@H:28]3[O:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:67][C@H:9]2[O:8][C:7](=[O:68])[NH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC[C@H]1CN(C(=O)OC(C)(C)C)CCO1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC[C@H]1CNCCO1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of the product from step 1 (92 mg) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) The resulting solution was stirred for 3 hours at room temperature until disappearance of the starting material. The solvent was removed in vacuo. The reaction mixture was dissolved in ethyl acetate and a saturated solution of sodium bicarbonate was added slowly. After extracting 3× with ethyl acetate, the combined organics were dried with sodium sulfate, filtered and concentrated to afford the desired product (77.9 mg). LRMS (ES+) m/z 865.45 (M+H)+.
Reaction SMILES: [CH:1]([CH2:3][NH:4][N:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[C:8](=[O:18])[C:7]([C:19]([O:21]CC)=[O:20])=[CH:6]1)=[O:2]>C(O)=O>[CH:1]([CH2:3][NH:4][N:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)=[O:2]
Reactant: CCOC(=O)c1cn(NCC=O)c2cc3c(cc2c1=O)OCO3
Solvent: O=CO
Product: O=CCNn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3

Procedure:
5-[(Formyl)methylamino]5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylic acid [V; R is CH3, R" is H] was prepared by heating ethyl 5,8-dihydro-5-[(formyl)methylamino]-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate (Example 6) with formic acid according to the procedure of Example 4, and was obtained in the form of colorless plates, m.p. above 330° C. when precipitated from a solution of its potassium salt by addition of acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:14]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)=[N:13][C:12]4[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:11]=4[NH:10][C:9]=3[S:27][C:4]=2[CH:3]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:28][CH2:26][C:24]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[S:27][C:9]=3[NH:10][C:11]=2[CH:25]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2c(c1)Nc1sc3cc(F)ccc3c1C(N1CCN(C)CC1)=N2
Solvent: ClC(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(CCl)cc3Nc3sc4cc(F)ccc4c32)CC1

Procedure:
3-Fluoro-8-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is dissolved in carbon tetrachloride and reacted with 2,2′-azobis(isobutylonitrile) in the presence of N-chlorosuccinimide to give 8-chloromethyl-3-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.