Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:19]([O:18][C:16](=[O:17])[NH:23][C@H:24]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][N:11]=1)[CH3:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: Nc1ccc(F)cc1Nc1ccncn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccncn1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To 4-fluoro-N2-pyrimidin-4-ylbenzene-1,2-diamine (0.247 g, 1.21 mmol), Boc-alanine (0.24 g, 1.27 mmol), and HOAT (0.165 g, 1.21 mmol) in DCM at 0° C. under nitrogen was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (0.244 g, 1.27 mmol). The reaction was stirred and allowed to warm to RT overnight. The mixture was diluted with DCM (20 mL) and washed with 0.5M NaHCO3 (20 mL). The organic extract was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-8% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated to give the title compound, (0.272 g, 60%) LCMS (Method J): RT=1.93 min, [M+H]+=376.20
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:28][C:27]([F:30])([F:29])[CH2:26]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:31])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[NH:84]1[CH2:89][CH2:88][O:87][CH2:86][CH2:85]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:27]1([F:29])[CH2:28][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:15]([CH3:31])=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([N:84]6[CH2:89][CH2:88][O:87][CH2:86][CH2:85]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:19]=3)[N:24]=2)[CH2:26]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(Br)ccn12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(N3CCOCC3)ccn12
Temperature: 110 °C

Procedure:
A mixture of 7-bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (42f) (50.0 mg, 0.10 mmol), Pd2(dba)3(9.2 mg, 0.01 mmol), rac-BINAP (18.7 mg, 0.03 mmol), NaOt-Bu (14.4 mg, 0.15 mmol) and morphline (17.4 mg, 0.2 mmol) in toluene (3 mL) was heated at 110° C. overnight. Once complete, the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-morpholinoimidazo[1,2-a]pyridine-3-carboxamide (F59). MS m/z 495.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[N:25](S(C3C=CC=CC=3)(=O)=O)[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([F:35])[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([F:35])[CH:5]=1
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A mixture of 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-3-fluoro-benzoic acid methyl ester (260 mg, 0.51 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3 ml) was stirred at 25° C. for 16 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-3-fluoro-benzoic acid methyl ester (160 mg, 85%) as a solid which was used in the next step without further purification; LC/MS m/e calcd for C22H21FN2O2 [M+H]+ 365.42, observed 365.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:16]1[C:15]([OH:17])=[N:14][N:13]2[C:12]=1[CH:11]=[N:10][N:9]=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1cc2cnnc(-c3ccccc3F)n2n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1nn2c(-c3ccccc3F)nncc2c1Br
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.2508 g, 1.09 mmol) in glacial acetic acid (5 ml) was added dropwise bromine (62 μl, 1.20 mmol) and the mixture was stirred at room temperature for 2.25 h. Water (20 ml) was then added and the resulting solid was collected by filtration, washed with water, and dried under vacuum at 50° C. to yield 0.3054 g (91%) of the title compound as a buff solid; 1H NMR (360 MHz, d6-DMSO) δ 7.43-7.50 (2H, m), 7.72 (1H, m), 7.80 (1H, m), 9.40 (1H, s), 12.67 (1H, s).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.O1CCCCC1OC1CCCCO1.Cl>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(CCO)c4)ccc2-3)n(C(C)C)n1

Procedure:
Similarly to as described in General Procedure C: 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranyl ether was accomplished by adding 2N HCl to the crude reaction mixture. Purification by reverse phase HPLC gave 287 as a colorless solid (53 mg). LCMS: 437.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:20](Cl)(=[O:22])[CH3:21]>C1COCC1>[C:20]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol) is added dropwise. The mixture is stirred at room temperature for 30 minutes. The mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated to yield 1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([CH:8]1[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:7].ClCCl.[OH-].[Na+]>O>[CH2:6]([C:8]1([CH:10]([CH3:9])[C:11]#[N:12])[C:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:16]=2[N:18]=[C:19]2[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]2)[CH2:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: CCC1CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(C(C)C#N)CCCN2CCC3=c4ccccc4=NC3=C21
Reaction time: 48 h
Yield: 79.4 %

Procedure:
10.0 g. (28.5 mmoles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3 -a)quinolizinium perchlorate are dissolved in 100 ml. of dichloromethane, and 75 ml. of distilled water and 20 ml. of 2 n sodium hydroxide are added to the solution under constant stirring in argon atmosphere. The reaction mixture is stirred for 10 minutes, thereafter the organic phase is separated and dried over anhydrous potassium carbonate. The drying agent is filtered off, 10 ml. (142 mmoles) of freshly distilled acrylonitrile are added to the filtrate, the mixture is flushed with argon, and allowed to stand at room temperature for 2 days, during which period the solution darkens considerably. Thereafter the solution is evaporated in vacuo under argon atmosphere (bath temperature: maximum 40° to 50° C). The residual dark red oil is triturated with 5 ml. of methanol, and the formed orange-red crystals are filtered off. The thus-obtained crude product, weighing 8.10 g., is recrystallized from 15-fold volume of methanol. 7.30 g. (79.4 %) of crystalline (1-ethyl-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinolizin-1-yl)-propionitrile are obtained; m.p.: 122-123° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:18])[N:7]3[C:19]([CH3:22])=[CH:20][S:21][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[CH3:3])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 50.8 %

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.105 g, 0.327 mmol) (1st peak from Example 23, step 1 chiral separation), 6-bromo-9H-purine (0.117 g, 0.588 mmol), and N,N-diisopropylethylamine (0.114 mL, 0.654 mmol) in ethanol (1.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.073 g, 51%). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1. Found: 440.0. 1H NMR (DMSO-d6, 500 MHz) δ 8.05 (2H, s), 7.34 (1H, br s), 7.18 (1H, m), 7.12 (2H, m), 6.84 (1H, s), 7.01 (1H, s), 5.07 (1H, m), 2.43 (3H, s), 1.31 (3H, d, J=7.0 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[CH:4]=[CH:5][C:6]2[C:15]=1[S:14](=[O:17])(=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[N:7]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[OH:18][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14](=[O:17])(=[O:16])[C:15]=2[C:2]=1[OH:1])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1C=CC2=Nc3ccccc3S(=O)(=O)C2=C1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)c2ccccc2Nc2ccc(O)c(O)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4-hydroxy-3H-phenothiazine-3-one-5,5-dioxide (0.8 g) in a mixture of water (20 ml) and ethyl acetate (20 ml) there was added sodium dithionite (2 g) and the resulting mixture was stirred at room temperature for 20 minutes. The insoluble solid was then filtered, washed with water and dried to afford the title compound, m.p. (dec.) 261° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.Cl.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]1[CH3:20].C(N(CC)CC)C.CO>C1COCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[C@@H:15]([CH3:20])[CH2:16]2)[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: C[C@H]1CNCCN1C
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 4,6-dichloro-5-fluoro-2-methylpyrimidine (0.181 g, 1.0 mmol) and (2S)-1,2-dimethylpiperazine dihydrochloride (0.189 g, 1.0 mmol) in THF (10 mL) was added triethylamine (0.42 mL, 3.0 mmol) at room temperature. MeOH (1 mL) was added to improve solubility. The reaction mixture was stirred overnight, and then the solvent was removed in vacuo. Ether, THF and water were added to the resulting residue. The organics were separated, dried (Na2SO4) and evaporated to provide 4-chloro-6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine as a yellow solid (0.254 g, 98%). LCMS: (M+H)+=259.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][NH:19][C:20]4[O:21][C:22]([C:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:26][CH3:27])=[N:23][N:24]=4)=[CH:15][CH:16]=3)[O:11][C:10](=[O:33])[CH:9]=2)=[CH:4][CH:3]=1.CI.[C:36]([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]([C:20]4[O:21][C:22]([C:25]([OH:32])([C:28]([F:30])([F:31])[F:29])[CH2:26][CH3:27])=[N:23][N:24]=4)[CH3:36])=[CH:15][CH:16]=3)[O:11][C:10](=[O:33])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(O)(c1nnc(NCc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(O)(c1nnc(N(C)Cc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1)C(F)(F)F
Temperature: 25 °C

Procedure:
The (−) isomer of 4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one (0.100 g, 0.22 mmol), methyl iodide (2 mL) and K2CO3 (0.061 g 0.44 mmol) were heated at 50° C. until the disappearance of starting material. The mixture was cooled to rt and diluted with EtOAc-water. The organic layer was separated, dried and the solvent removed. Purification on silica gel (toluene-acetone, 8:2) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 7.68 (m, 2H), 7.51 (d, 1H), 7.48 (s, 1H), 7.39 (m, 3H), 6.49 (s, 1H), 6.12 (s, 1H), 4.8 (q, 2H), 3.17 (s, 3H), 2.26 (m, 1H), 2.09 (m, 1H), 1.02 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylxanthine (2.882 g) was suspended in N,N-dimethylformamide (40 ml), and potassium carbonate (3 g) and benzyl bromide (2.5 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The deposited crystals were collected by filtration and washed with ethyl acetate to give 3.18 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:9](CCCCSC(=N)N)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[OH-].[Na+]>[CH2:10]([NH:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)SCCCCN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(CNCc2ccccc2)cc1

Procedure:
S-[(N,N-dibenzyl)aminobutyl]isothiourea, hydrochloride (prepared according to Example 15) was hydrolysed in aqueous ethanolic sodium hydroxide. The solvents were evaporated and the residue taken up in water and extracted 3 times with methylene dichloride. The extracts were dried (MgSO4), filtered and evaporated to give N-(3-mercaptopropy])dibenzylamine.
Reaction SMILES: [N:1]1[C:6]2[O:7][CH2:8][C:9](=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH3:11][O:12][NH2:13].CC([O-])=O.[Na+]>CCO>[CH3:11][O:12][N:13]=[C:9]1[C:5]2[CH:4]=[CH:3][N:2]=[N:1][C:6]=2[O:7][CH2:8]1
Reactant: O=C1COc2nnccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C1COc2nnccc21
Temperature: 30 °C

Procedure:
To a solution of furo[2,3-c]pyridazin-5(6H)-one (4.81 mmol) in 30 mL EtOH were added O-methyl-hydroxylamine (9.62 mmol) and NaOAc (9.62 mmol). After heating to 30° C. for 4.5 h the reaction mixture was concentrated in vacuo to half of its volume. Water and DCM were added and the aqueous phase was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as beige solid;
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[CH:20][O:21]C)(O)[CH:10]=[CH2:11].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[F:28][C:26]([F:29])([F:27])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]1([CH:10]=[CH2:11])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:19][CH2:20][O:21]1
Reactant: C=CC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C=COC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3,5-bis(trifluoromethyl)benzyloxy)-2-(2-(2-methoxyvinyl)phenyl)but-3-en-2-ol (190 mg, 0.426 mmol) and triethylsilane (0.27 mL, 1.7 mmol) in dichloromethane (4 mL) at −78° C. was added boron trifluoride etherate (0.11 mL, 0.85 mmol) dropwise. The ice bath was removed after 10 min, stirred at room temperature for 30 min, recooled to −78° C., and quenched by addition of saturated sodium bicarbonate. The mixture was extracted with diethyl ether (2×) which was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (3%-->10% EtOAc/Hex) gave 125 mg (71%). 1H-NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 7.64 (s, 2H), 7.20 (m, 2H), 7.13 (m, 2H), 6.04 (dd, J=17.1, 10.7 Hz, 1H), 5.31 (dd, J=10.7, 1.2 Hz, 1H), 5.20 (dd, J=17.4, 1.5 Hz, 1H), 4.67 (qAB, JAB=13.4 Hz, 2H), 4.04 (ddd, J=11.3, 5.5, 2.4 Hz, 1H), 3.87 (ddd, J=11.0, 11.0, 3.4 Hz, 1H), 3.79 (qAB, JAB=10.4 Hz, 2H), 3.04 (ddd, J=16.5, 11.0, 5.8 Hz, 1H), 2.64 (ddd, J=16.2, 2.7, 2.7 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 141.4, 139.1, 135.9, 135.2, 131.6 (q, J=33.6 Hz), 129.2, 127.3, 126.9, 126.4, 126.0, 123.5 (q, J=273 Hz), 121.4, 117.4, 80.0, 77.6, 72.2, 60.3, 29.4. Mass spec.: 439.25 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]=[C:22]1[NH:28][C:27]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[CH:32][C:26]=2[C:25](=[O:36])[NH:24][CH2:23]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:33]([C:30]1[CH:31]=[CH:32][C:26]2[C:25](=[O:36])[NH:24][CH2:23][C:22](=[O:21])[NH:28][C:27]=2[CH:29]=1)=[O:34]
Reactant: O=C1CNC(=O)c2ccc(C(=O)O)cc2N1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)NC(=O)CNC2=O

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid. MS: 476.3 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[N:13]2[C:8]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)=[N:7]1.[I-].[K+].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:26]2[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=2[NH:24]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[O:22]=[C:23]1[N:27]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14](=[O:15])[N:13]4[C:8]([CH2:9][O:10][C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=54)=[N:7]3)[CH2:32][CH2:33]2)[C:26]2[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=2[NH:24]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=c1n(CCCCCl)nc2n1-c1ccccc1OC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)nc2n1-c1ccccc1OC2
Reaction time: 4.75 h

Procedure:
A solution of 2-(4-chlorobutyl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one, (1.40 g., 0.005 mole), potassium iodide (0.83 g.; 0.005 mole) and 4-(2-keto-1-benzimidazolinyl)piperidine (2.39 g.; 0.011 mole) in 25 ml. of DMF was warmed to 115° C. and stirred for 4.75 hours. The resulting solution was cooled, poured into saturated sodium bicarbonate aqueous solution and extracted with methylene chloride. The methylene chloride extracts were combined and washed with brine solution, dried over sodium sulfate and concentrated in vacuo. The resulting residue was crystallized from ethyl acetate to give 1.87 g., m.p. 173°-175.5° C. and 0.03 g., m.p. 172°-173° C. of the above named end product. The analytical sample had melting point 174°-175.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]([CH3:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([N:17]([CH3:26])[CH3:16])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(N(C)C)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(N(C)C)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N,N-dimethyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][O:37][C:38]1[N:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:41]3[CH:42]=[N:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: COc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](CN)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and (6-methoxypyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.92 min, m/z=488.0 [M+H]+.