Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:27][C:26](=O)[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10]3[CH:4]2[C:3]1=O.B#B.Cl>O1CCCC1.CO>[CH3:1][N:2]1[CH2:27][CH2:26][N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10]3[CH:4]2[CH2:3]1
Reactant: COC(=O)c1c2n(c3ccccc13)Cc1ccccc1N1C(=O)CN(C)C(=O)C21
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c2n(c3ccccc13)Cc1ccccc1N1CCN(C)CC21

Procedure:
A mixture of methyl 1,3,4,16b-tetrahydro-2-methyl-1,4-dioxo-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate (1.48 kg) in tetrahydrofuran (52 L) is heated to reflux under an atmosphere of nitrogen and then a solution of diborane in tetrahydrofuran (1M, 9.47 L) is added over a period of one hour. The reaction mixture is maintained at reflux for 20 hours, at which time it is treated sequentially with methanol (4 L) (slow, cautious addition) and a solution of hydrogen chloride in methanol (7.5N, 1.6 L). The mixture is stirred, refluxed for 2 hours and evaporated in vacuo, and the solid residue obtained is triturated with acetone (4 L) for 1 hour, collected, washed with acetone (4×500 ml) and dried (18 hours, 50°/0.5 mm Hg) to yiled methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate hydrochloride, mp 272°-273° . This salt is suspended in dichloromethane and sufficient ammonium hydroxide (28%) in water is added to liberate the free base. The basic mixture is stirred for 45 minutes, the aqueous layer is removed and discarded and the organic layer is washed with water. The dichloromethane is evaporated in vacuo and the residual foam dissolved in boiling 2-propanol. The solution is filtered to remove a small amount of insolubles, then allowed to cool overnight for complete crystallization. The obtained solid is purified by recrystallization from 2-propanol. The solution is allowed to cool gradually while stirring overnight. The resulting crystals are collected by filtration, washed with 2-propanol and dried (16 hours, 80°/3 mm Hg) to yield methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate, mp 157°-159°, the compound of formula I wherein R1 is methyl, R2 and R3 are hydrogen and R4 is methoxycarbonyl.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(#N)C>[CH:1]1([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[O:15])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(NC2CCCC2)ncn1
Reactant: Nc1ccc(O)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(O)cc1)c1cc(NC2CCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopentyl)amino]pyrimidine-4-carboxylic acid (Intermediate 5) and 4-aminophenol (Aldrich), the title compound was obtained as a yellow solid after trituration in acetonitrile. 1H NMR (300MHz, DMSO-d6) δ [ppm] 10.22 (1H, s), 9.32 (1H, s), 8.52 (1H, s), 7.85 (1H, d, J=7.0 Hz), 7.62 (2H, d, J=9.0 Hz), 7.13 (1H, s), 6.72 (2H, d, J=9.0 Hz), 4.28 (1H, m), 1.94 (2H, m), 1.74-1.40 (6H, m). MS (ESI+): 299.1. HPLC (Condition A): Rt 2.17 min (HPLC purity 96.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.O(C)[Li].[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31][CH:30]=1>>[OH:36][CH:35]([C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:7][C:6]=2[CH:22]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Li]OC
Product: O=C(O)c1cc(C(O)c2ccncc2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 g, 2.52 mmol, 1 eq.), LiOMe (192 mg, 5.04 mmol, 2 eq.) and pyridine-4-carbaldehyde (0.48 mL, 5.03 mmol, 2 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, CH2Cl2/MeOH 92:8→80:20) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([O:23]CC)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 22A in analogy to the synthesis of the compound of Example 71A. 4.18 g (78% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25]C)[CH:12]=3)[C:3]=12.B(Br)(Br)Br>C(Cl)Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:27]([CH3:28])[CH3:29])[N:9]=2)=[CH:12][C:13]=1[OH:25]
Reactant: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccc(N)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
BA20 (tert-butyl 4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenylcarbamate, 7 mg, 0.018 mmol) was dissolved in CH2Cl2 (2.5 ml) and stirred under an argon atmosphere at room temperature. BBr3 (0.500 ml) was added slowly with a syringe. The reaction mixture was stirred overnight, under argon at room temperature. BBr3 was removed in vacuo and the remaining solid was purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA20dd.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=O)=O)=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.S(OC)(O[CH3:26])(=O)=O.[OH-].[Na+]>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:26])=[CH:7][CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: O=S(=O)(Cl)c1ccc(CCCCl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CSc1ccc(CCCCl)cc1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
At room temperature, a solution of 10b (12.7 g; 5.0 mmol) in diethyl ether (75 ml) was added dropwise over a period of 2.5 h to a suspension of LiAlH4 (2.9 g; 7.6 mmol) in diethyl ether (50 ml). After the addition had ended, the reaction mixture was stirred at room temperature and with occasional addition of LiAlH4 until no more starting material could be detected by thin-layer chromatography (2.5 h). With ice-cooling, ice was introduced into the reaction mixture, and the aqueous phase was acidified with 10% hydrochloric acid (pH 1). The organic phase was removed and the aqueous phase was extracted with diethyl ether (3×). The combined organic extract was washed with 10% strength aqueous sodium hydroxide solution (4×50 ml) until it was virtually colorless. Dimethyl sulfate (9.0 g; 7.0 mmol) was added to the combined sodium hydroxide extract, and the mixture was stirred at room temperature for 16.5 h. The oily sediment was taken up in diethyl ether. The organic phase was separated off and the aqueous phase was again extracted with diethyl ether (2×). The combined organic extract was dried over Na2SO4 and concentrated. The brown oily residue was subjected to a kugelrohr distillation (0.2 mbar, 250° C.).
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.BrCCCC1C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)N)=[CH:24][CH:23]=1.C(OC(OCC)CCCNC)C.ClC1C=C2[C:58](=CC=1)[N:57]([CH2:61][CH2:62][CH2:63][C:64]1[CH:69]=CC=CC=1)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:21][C:22]1[CH:27]=[C:26]2[C:25](=[CH:24][CH:23]=1)[N:28]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:64]1[CH2:69][N:57]([CH3:58])[CH2:61][CH2:62][C:63]2=1
Reactant: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Reactant: CNCCc1cn(CCCc2ccccc2)c2ccc(Cl)cc12
Agent: BrCCCc1ccccc1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCc2c(n(CCCc3ccccc3)c3ccc(Cl)cc23)C1

Procedure:
The title compound was prepared by following General Methods 2, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 1-(3-bromopropyl)benzene, and tetra-n-butylammonium chloride (General Method 2), 1-(4-chlorophenyl)-1-(3-phenylpropyl)hydrazine (Example 9) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(3-phenylpropyl)-1H-indol-3-yl)-N-methylethanamine (Example 18), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Br[CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCN(C2CCCC2)CC1
Reaction time: 30 h

Procedure:
To a stirred and warm (40° C.) mixture of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of n.butanol is added 3.75 parts of bromocyclopentane and the whole is stirred and refluxed for 21h. 30. Then a second portion of 5 parts of bromocyclopentane is added and stirring at reflux temperature is continued for another 30 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The oily residue solidifies on triturating in 1,1'-oxybisethane. The solid product is filtered off and crystallized from 1,1'-oxybisethane, yielding 1.1 parts of N-(4-chlorophenyl)-N-(1-cyclopentyl-4-piperidinyl)benzeneacetamide; mp. 139.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([OH:17])=[C:12]([F:18])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1.[H-].[Na+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[C:12]([F:18])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(Oc2ccc(C#N)cn2)c(F)c1
Yield: 51 %

Procedure:
A solution of phenol obtained in step 3 above (1.31 g, 4.8 mmol), 6-chloronicotinonitrile (700 mg, 5.04 mmol) and sodium hydride (290 mg, 7.2 mmol) in DMSO (25 mL) is stinted at room temperature for 18 hours. Pour the mixture into iced water and extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4, filtrate and eliminate the solvent. Purify by flash chromatography (EtOAc/hexane 20/80 and 34/66) to get the title compound (950 mg, 51%). 1H-NMR (CDCl3, 200 MHz): 8.41 (dd, 1H, J=0.8 and 2.1 Hz), 7.97 (dd, 1H, J=2.4 and 8.6 Hz), 7.18 (dd, 1H, J=0.8 and 8.6 Hz), 6.92-6.81 (m, 2H), 3.39 (q, 2H, J=6.9 Hz), 2.81 (t, 2H, J=6.7 Hz), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3OCCO3)=[CH:7][C:5]=2[CH:6]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]=[C:20]3[S:16][C:17](=[O:22])[NH:18][C:19]3=[O:21])=[CH:7][C:5]=2[CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: Clc1cc2cc(C3OCCO3)ccc2o1
Product: O=C1NC(=O)C(=Cc2ccc3oc(Cl)cc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 2-Chloro-5-[1,3]dioxolan-2-yl-benzofurane (intermediate 67) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[OH:15][C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[OH:15][C:16]1[N:20]([CH3:21])[N:19]=[CH:18][C:17]=1[C:12]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: Cn1nccc1O
Reactant: Cc1ccc(C(=O)Cl)c2cccnc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)c2cnn(C)c2O)c2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 1.70 g of 8-methylquinoline-5-carbonyl chloride were added to 0.81 g of 5-hydroxy-1-methylpyrazole and 0.92 g of triethylamine in 30 ml of acetonitrile. The reaction mixture was stirred for 3 hours at room temperature and then taken up in ethyl acetate and washed with aqueous sodium carbonate solution, and the organic phase was then dried and concentrated. The residue was treated with 10 ml of dioxane and 1.71 g of dry potassium carbonate and heated under reflux for 14 hours. After cooling, water was added and the aqueous phase was washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitate was filtered off under suction and the acidified aqueous phase was extracted with ethyl acetate. This organic phase was dried and concentrated. The residue and the precipitate were combined.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:50])[CH2:30][C:31]2([CH2:46][N+:47]([O-:49])=[O:48])[CH2:36][CH2:35][CH:34]([CH2:37][NH:38]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2OC3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1[O:51]C)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:38][CH2:37][CH:34]1[CH2:35][CH2:36][C:31]([CH2:30][C:29]([NH:28][C@H:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:53])[C:8]=3[O:51][B:15]2[OH:16])=[O:50])([CH2:46][N+:47]([O-:49])=[O:48])[CH2:32][CH2:33]1
Reactant: COc1c(CC(NC(=O)CC2(C[N+](=O)[O-])CCC(CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCC1CCC(CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)(C[N+](=O)[O-])CC1

Procedure:
Prepared from 3-[2-{2-[4-(tert-Butoxycarbonylamino-methyl)-1-nitromethyl-cyclohexyl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 420 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(C=Cc1ccccc1O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccccc1CCC(O)c1ccccc1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
2-Hydroxychalcone (28.5 g) was stirred with ethanol (500 ml) whilst sodium borohydride (9.45 g) was added in small portions. The solution, which turned from red to pale yellow was allowed to stand overnight at room temperature, then the solvent was evaporated off and the residue extracted with dichloromethane, washing with water. Evaporation of the solvent yielded 3-(o-hydroxyphenyl)-1-phenylpropan-1-ol (24.4 g). 1.0 g of this carbinol was dissolved in concentrated sulphuric acid, and the solution was allowed to stand at room temperature for 2 hr. The solution was poured into iced water, and the sticky orange product filtered off, washed with water, dried, and chromatographed on alumina, eluting with toluene. Evaporation of the eluate gave flavan (0.20 g), which was recrystallised from petroleum ether, b.p. 40°-60°, to give flavan m.p. 42°-43°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH2:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:31][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1cccc2ccccc12
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1cccc2ccccc12
Yield: 73.2 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 1-naphthylamine (150 mg, 1.05 mmol)to give 170 mg of the title compound (73%): mp 171°~172° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 10.02 (s, 1H), 8.01~8.05 (m, 1H), 7.92~7.97 (m, 1H), 7.78 (d, 1H, J=7.9 Hz), 7.70 (d, 1H, J=6.9 Hz), 7.52~7.61 (m, 2H), 7.49 (d, 1H, J=7.6 Hz), 7.28 (s, 1H), 7.20 (s, 1H), 5.26~5.36 (m, 1H), 3.18 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.91 (dm, 1H, J=17.1 Hz), 2.73~2.85 (m, 2H), 2.17~2.29 (m, 1H), 1.89~2.09 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[NH2:12])=[CH:5][CH:4]=1.[OH:13][CH:14](C(O)C([O-])=O)[C:15]([O-])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:14](=[O:13])[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2C[C@H]2N)cc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Product: COc1ccc([C@@H]2C[C@H]2NC(C)=O)cc1

Procedure:
The sub-title compound was prepared according to the method of Example 4, step a) from (1R-trans)-2-(4-methoxyphenyl)cyclopropanamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described in W09905143) to give a white solid (655 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].C1C=C[NH+]=CC=1.[Br:22][Br-]Br>C1COCC1>[Br:22][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:4]=1)[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(=O)C(Br)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 8 h

Procedure:
A stirred solution of 2-chloro-5-(2-oxo-propyl)-benzenesulfonamide (33a) (1.4 g, 5.7 mmol) in dry THF (100 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (2.9 g, 5.7 mmol) and left to stir overnight. The reaction mixture is then filtered and the solvent removed in vacuo. The residue is purified by chromatography on silica eluting with 1:4 ethyl acetate-hexane to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:11][N:10]([C:25]2[CH:30]=[CH:29][C:28](=[O:31])[NH:27][N:26]=2)[N:9]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]([F:24])([F:22])[F:23])[CH:14]=2)=[CH:11][N:10]([C:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][N:26]=2)[N:9]=1
Reactant: O=c1ccc(-n2cc(-c3ccnc(NCC(F)(F)F)c3)c(-c3ccccc3F)n2)n[nH]1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: O=C1CCC(n2cc(-c3ccnc(NCC(F)(F)F)c3)c(-c3ccccc3F)n2)=NN1
Yield: 62.9 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 243 mg (0.57 mmol) of 3-(2-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-4-[2-(2,2,2-trifluoroethyl)aminopyridin-4-yl]-1H-pyrazole obtained in Example 34-2) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 155 mg of the title compound as a beige powder. (Yield: 64%)
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[C:17]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])[N:16]=2)=[O:14])=[CH:11][C:10]=1[O:36][CH3:37]>N1C=CC=CC=1.ClCCl>[CH3:37][O:36][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:9]=1[NH:8][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[C:17]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[N:16]=1)=[O:14]
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(N)c(OC)c3)n3ccccc23)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.17 ml (1.5 mmol) of 1-propanesulfonyl chloride is added to 0.5 g (1.24 mmol) of methyl 3-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]benzoate obtained in example 111 in 6 ml of pyridine. The reaction medium is stirred at ambient temperature for 18 h and then concentrated under reduced pressure. The residue obtained is taken up in dichloromethane. The organic phase obtained is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.34 g of a yellow oil is collected. MS+: 508; 1H NMR (d6-DMSO): 0.96-1.01 (3H, t), 1.74-1.81 (2H, m), 3.16-3.19 (2H, m), 3.92 (3H, s), 4.00 (3H, s), 7.33-7.73 (2H, m), 7.38-7.51 (1H, m), 7.53-7.96 (2H, m), 8.03-8.30 (2H, m), 8.33-9.85 (2H, m), 8.38 (1H, s), 8.63 (1H, s), 9.25 (1H, m)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]=[CH:15][C:14]4[CH2:20][N:21]([CH3:31])[C:22](=[O:30])[N:23]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:13]=4[C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[C:32](O)(=[O:36])[C@@H:33]([CH3:35])[OH:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.ClCCl.C(N(CC)CC)C>[OH:34][C@H:33]([CH3:35])[C:32]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[C:13]3[C:12]4[N:11]=[C:10]([C:7]5[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=5)[CH:19]=[CH:18][C:17]=4[N:16]=[CH:15][C:14]=3[CH2:20][N:21]([CH3:31])[C:22]2=[O:30])[CH2:25][CH2:26]1)=[O:36]
Reactant: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCNCC2)C(=O)N(C)C4)cn1
Reactant: C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)[C@@H](C)O)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
9-(6-methoxypyridin-3-yl)-3-methyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-2(1H)-one hydrochloride (hydrochloride of Compound 114 (100 mg, 0.227 mmol)) and triethylamine (0.177 mL) were added to dichloromethane (20 mL), stirred at room temperature for 0.5 h, then to the system sequentially added (R)-lactic acid (26.7 mg, 0.296 mmol), 1-hydroxybenzotriazole (37.8 mg, 0.280 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (70.8 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 2 h. After confirming the reaction was completed by a thin layer chromatography plate (dichloromethane:methanol=10:1), the reaction liquid was washed sequentially with a saturated aqueous solution of sodium carbonate, water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to give 88 mg of a white solid.