Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3[C:17]([F:20])([F:19])[F:18])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:5]12[N:8]([C:9]3[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=3[C:17]([F:20])([F:18])[F:19])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: N#Cc1ccc(N2C3CCCC2CC3)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(N2C3CCCC2CC3)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(8-Azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzonitrile in THF (50 mL) was treated with solid LAH (0.68 g, 18 mmol) at 0° C. portionwise. The mixture was heated at reflux 1 hour, allowed to cool to 0° C., and quenched by addition of (Na2SO4 10H2O). The mixture was stirred 30 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% to 10% MeOH/CH2Cl2 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.57 (d, 1H, J=2.0 Hz), 7.42 (dd, 1H, J=8.1, 2.0 Hz), 7.08 (d, 1H, J=8.4 Hz), 3.658 (m, 4H), 2.15 (bs, 2H), 1.92 (m, 2H), 1.88-1.55 (m, 5H), 1.48 (m, 3H); MS (ESI) 268 (M−NH2)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[S:7]([CH3:18])([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:8])=[O:5])[CH3:2].[OH-].[Na+].O.C(OCC)(=O)C>C1COCC1.Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:7]([CH3:18])(=[N:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:8])=[CH:10][CH:11]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 8.70 g (32.0 mmol) of (RS)—N-(ethoxycarbonyl)-S-methyl-S-(4-nitrophenyl)sulfoximide in 650 ml of THF is slowly mixed at room temperature with 435 ml of a 10% solution of Ti(III)Cl in approximately 10% hydrochloric acid (Aldrich). The batch is stirred for 4 hours at room temperature and then cooled to 0° C. 450 ml of a 32% NaOH solution is added in drops. In this case, the reaction mixture is now diluted by the addition of water and ethyl acetate. It is mixed with 500 ml of ethyl acetate, and the organic phase is separated. The pulpy, aqueous phase is extracted from ethyl acetate. The combined organic phases are washed with dilute NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. 8.05 g (about 32.0 mmol) of the product is obtained, and said product is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: OC1CCNC1
Product: OC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 3-pyrrolidinol (42.3 mg; 0.48 mmol) to give Example 142 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.62-7.59 (2H, m), 7.56-7.47 (4H, m), 4.73 (1H, d, J=4.5 Hz), 4.26-4.20 (1H, m), 3.72-3.61 (2H, m), 2.73 (1H, dd, J=9.7, 6.2 Hz), 2.63 (1H, q, J=7.8 Hz), 2.49-2.46 (1H, m), 2.36 (1H, dd, J=9.5, 3.7 Hz), 2.09-1.99 (1H, m), 1.63-1.55 (1H, m). LC/MS (Method C): 484 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 99.9%).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[F:45][CH:46]([F:51])[CH:47]1[CH2:50][NH:49][CH2:48]1.CN1CCOCC1>CN(C=O)C>[F:45][CH:46]([F:51])[CH:47]1[CH2:50][N:49]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:48]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: FC(F)C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)[C@H](C(=O)N1CC(C(F)F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 3-(Difluoromethyl)azetidine (8.27 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-60% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (9.8 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 0.78 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 2.31-2.39 (m, 1H), 2.99-3.15 (m, 1H), 3.77-4.35 (m, 4H), 4.82-5.11 (m, 3H), 6.10-6.41 (m, 1H), 7.98 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.39 (s, 1H). [M+H] calc'd for C18H19F3N4O2, 381; found, 381.
Reaction SMILES: [CH:1]1(NCCC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]1([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>>[CH:1]1([CH2:19][CH2:20][CH2:21][NH:22][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCNC1CCCCC1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCC4CCCCC4)CC3)cc2o1

Procedure:
Condensation of cyclohexyl-1-propylamine (0.9 g, 6.4 mmol) and ketone 5 (1.5 g, 6.4 mmol), following the procedure described in Example 1, gave 6-{trans-4-[(3-cyclohexylpropyl)amino]cyclohexyl}-3H-benzoxazol-2-one (352 mg, 15%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.12 (br s, 1H), 6.97-6.93 (m, 2H), 3.70-3.10 (br s, 2H), 2.53 (t, J=7 Hz, 2H), 2.48-2.39 (m, 2H), 1.95 (br d, J=12 Hz, 2H), 1.77 (br d, J=12 Hz, 2H), 1.70-1.59 (m, 5H), 1.50-1.38 (m, 4H), 1.23-1.08 (m, 8H), 0.90-0.81 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[CH:19][C:18]=1OS(C(F)(F)F)(=O)=O)([O-:16])=[O:15].S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[CH:21][C:22]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])([O-:16])=[O:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a suspension of 60% sodium hydride (5.8 g, 145 mmol) in DMF (150 mL) was added diethyl malonate (26.4 mL, 175 mmol) at room temperature, while the sodium hydride was washed with dry hexane before use. The mixture was heated at 40° C. for 1.5 h, allowed to cool at room temperature and 1-nitro-4-phthalimidomethyl-2-trifluoromethanesulfonyloxybenzene (25 g, 58 mmol) was added. The mixture was stirred overnight at room temperature, poured into 3% potassium hydrogen sulfate, and extracted with a 1:1 toluene/ethyl acetate. The extract was washed successively with 5% potassium hydrogen sulfate, water, saturated aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated. The unreacted diethyl malonate was distilled out in vacuo and the residual solid was washed with 1:1 diethyl ether/hexane to give 24.5 g of the title compound: 1H NMR (CDCl3) δ8.04 (d, 1H, J=8.9 Hz), 7.85~7.90 (m, 2H), 7.72~7.78 (m, 2H), 7.56 (d, 1H, J=8.9 Hz), 7.54 (s, 1H), 5.24 (s, 1H), 4.90 (s, 2H), 4.27 (q, 4H, J=7.3 Hz), 1.28 (t, 6H, J=7.3 Hz).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C.CO>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:31]=[CH:30][C:29]([C:27]([O:26][CH3:25])=[O:28])=[N:34][CH:33]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2cnc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 87 %

Procedure:
5-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile (for a preparation, see Intermediate 51) (390 mg, 1.010 mmol), (6-(methoxycarbonyl)pyridin-3-yl)boronic acid (219 mg, 1.21 mmol), PdCl2(dppf) (111 mg, 0.151 mmol) and triethylamine (0.281 ml, 2.02 mmol) were combined in a mixture of dry MeOH (6 mL) and DME (1 mL). The mixture was heated under microwave irradiation to 120° C. for 45 mins. The mixture was then concentrated in vacuo and the residue purified by chromatography (100 g column, EtOAc/cyclohexane gradient) to give methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (389 mg, 0.879 mmol, 87% yield) as a pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:19][C:20](OC(C)(C)C)=[O:21])[OH:18].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:19][CH2:20][OH:21])[OH:18]
Reactant: CC(C)(C)OC(=O)CC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of tert-butyl 2-(7-bromo-3-chloro-1-fluoro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (66 g, 148 mmol) in THF (200 mL) was cooled to −78° C. followed by the drop wise addition of diisobutylaluminum hydride (1.0 M solution in THF; 180 ml, 180 mmol). The resulting reaction mixture was cooled to 0° C. and stirred for 2 h. The reaction mixture was quenched with aqueous, saturated NH4Cl solution and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by chromatography (0-50% EtOAc/hexanes) to afford 7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-ol (48 g, 128 mmol, 86% yield) as a light yellow solid.
Reaction SMILES: [N+:1](=[C:3]1[N:7]=[CH:6][N:5]=[C:4]1[C:8]([NH2:10])=[O:9])=[N-:2].[N:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]=[O:13]>CS(C)=O>[CH3:19][S:16]([CH2:15][CH2:14][N:11]1[C:12](=[O:13])[N:7]2[CH:6]=[N:5][C:4]([C:8]([NH2:10])=[O:9])=[C:3]2[N:1]=[N:2]1)(=[O:18])=[O:17]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CS(=O)(=O)CCN=C=O
Solvent: CS(C)=O
Product: CS(=O)(=O)CCn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-diazoimidazole-4-carboxamide (0.5 g, 12.0 mmol) in dry DMSO (5 mL) was added 1-Isocyanato-2-methanesulfonyl-ethane (1.04 g, 3.65 mmol). The mixture was stirred at room temperature for 16 hours, whereupon it was poured onto crushed ice and the resultant precipitate collected by filtration. The filter cake was washed with Et2O (3×1 reaction volume) and dried to give the title compound as an off white solid (990 mg, 95%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.89 (1H, s), 7.84 (1H, s), 7.71 (1H, s), 4.73 (2H, t, J=6.8 Hz), 3.70 (2H, t, j=6.8 Hz), 2.44 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCC1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][CH2:10][CH:11]=[CH2:12])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: C=CCCC(=O)c1cccc(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: C=CCCC(=C1C(=O)Nc2cc(Cl)ccc21)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 1-(3-chlorophenyl)pent-4-en-1-one (Example 62, Step A) (14.86 g, 76 mmol) and 6-chloroindolin-2-one (12.79 g, 76 mmol) in toluene (50 mL) at room temperature was added pyrrolidine (6.31 mL, 76 mmol). The slurry was heated at reflux with a Dean Stark trap for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 10 to 20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:7]=[C:8]([N:12]=[C:13]=[S:14])[CH:9]=[CH:10][CH:11]=1>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=1)=[S:14])#[N:1]
Reactant: N#CN
Reactant: S=C=Nc1cccc(Cl)c1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly treated with 3-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (5.4 g), m.p. 258°-260° C.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21]([C@@H:23]1[O:25][CH2:24]1)Cl>CC(O)C>[O:25]1[CH2:24][C@H:23]1[CH2:21][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Temperature: 85 °C
Yield: 52.7 %

Procedure:
To a solution of 4-Hydroxycarbazole (10.98 g, 0.06 mole) dissolved in IPA (60 mL) was added K2CO3 (20.73 g, 0.15 mole), followed by (R)-(−)-epichlorohydrin (7 ml, 0.09 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was cooled to room temperature, worked up and purified following the procedure similar to one described in step I for the synthesis of example 23, to afford the desired compound as a light brown colored solid (7.56 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:12](=O)(=[O:15])([OH:14])[OH:13]>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
145 g of 1-Chloroisoquinoline was dropwise added to 500 g of 60% fuming sulfuric acid while cooling with ice. Then, the temperature was elevated to 80° C. and the reaction was effected while stirring for 18 hours. The obtained reaction mixture was added to 1 kg of ice water, followed by stirring for 2 hours at 5° C. to precipitate crystals. The thus obtained crystals were separated by filtration, washed with 100 ml of methanol and then with 100 ml of ether, and dried under reduced pressure to obtain 126 g of 1-chloro-5-isoquinolinesulfonic acid. The compound was analyzed to give the following data.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:14])[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH2:8].[P:15]([O-:20])([O:18][CH3:19])[O:16][CH3:17]>>[CH3:17][O:16][P:15]([CH2:8][CH:7]([C:6]([O:5][CH3:4])=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:20])[O:18][CH3:19]
Reactant: COP([O-])OC
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(CP(=O)(OC)OC)C(=O)OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
8 ml of a 30% sodium methylate solution are added dropwise to 158 g (1 mol) of itaconic acid dimethyl ester and 110 g of dimethyl phosphite at 60° C. The exothermic reaction is by that time completed. The mixture is then stirred for one hour at 100° C. and concentrated by evaporation. Quantitative yield of a colorless liquid.
Reaction SMILES: [N:1]1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].N.[Cl-].[Na+]>CN(C)C=O.CO.O>[NH2:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH2:1])=[O:36]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: NC(=O)c1ccc(F)cc1N
Yield: 89.7 %

Procedure:
59.23 g (0.387 mol) of benzotriazol-1-ol, 65.776 ml (0.387 mol) of N-ethyldiisopropylamine and 74.15 g (0.387 mol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added successively at room temperature to a solution of 50.0 g (0.322 mol) of 2-amino-4-fluorobenzoic acid in 600 ml of dimethylformamide. 64.46 ml (0.451 mol) of ammonia in methanol (7 mol/l) were added dropwise with stirring, and the mixture was stirred for 18 hours. Water (2 l) and concentrated sodium chloride solution (0.5 l) were added to the batch. The mixture was extracted three times with ethyl acetate (0.75 l each time). The organic phase was dried over sodium sulfate, filtered, and the solvent was subsequently stripped off in a Rotavapor. The residue was triturated with 2-methoxy-2-methylpropane (0.2 l) and ligroin (0.1 l). The crystalline precipitate was filtered off with suction and dried in a drying cabinet, giving 44.5 g of 2-amino-4-fluorobenzamide as solid. 35.85 g (0.520 mol) of sodium nitrite in 75 ml of water were added dropwise at room temperature to a suspension of 44.5 g (0.289 mol) of 2-amino-4-fluorobenzamide in 1.4 l of hydrochloric acid (25%). The mixture was stirred for 2 hours with ice-cooling. The deposited precipitate was filtered off with suction, rinsed with water and dried at 60° C. in a vacuum drying cabinet, giving 32.58 g of 7-fluoro-3H-benzo[d]-1,2,3-triazin-4-one as solid; HPLC/MS (M+H)+=166; 1H NMR (300 MHz, DMSO) δ 8.32 (dd, J=8.8, 5.7, 1H), 7.87 (dd, J=9.0, 2.5, 1H), 7.64 (td, J=8.7, 2.5, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])O[CH:9]=[CH:8]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]1>>[OH:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:34]([C:22]1[CH:23]=[CH:24][C:25]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)=[C:20]([O:19][CH3:18])[CH:21]=1)[CH:9]=[CH:8]2
Reactant: CC[C@H](O)COc1ccc2c(=O)occc2c1
Reactant: COc1cc(N)ccc1N1CCCN(C)CC1
Product: CC[C@H](O)COc1ccc2c(=O)n(-c3ccc(N4CCCN(C)CC4)c(OC)c3)ccc2c1

Procedure:
6-((S)-2-Hydroxy-butoxy)-isochromen-1-one and 3-methoxy-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamine were reacted according to Method AJ. In this way the product was obtained with molecular weight 451.57 (C22H33N3O4); MS (ESI): 452 (M+H+).
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][C:12]3[N:13]([CH:16]=[C:17]([C:19](OC)=[O:20])[N:18]=3)[C:14]=2[N:15]=1.ClC1C=CC2OCCC3[N:34](C=C(C(OC)=O)N=3)C=2N=1.CC(C#C)CO.N.O>O1CCOCC1.O>[OH:1][C:2]([CH3:23])([CH3:24])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][C:12]3[N:13]([CH:16]=[C:17]([C:19]([NH2:34])=[O:20])[N:18]=3)[C:14]=2[N:15]=1
Reactant: COC(=O)c1cn2c(n1)CCOc1ccc(Cl)nc1-2
Reactant: COC(=O)c1cn2c(n1)CCOc1ccc(C#CC(C)(C)O)nc1-2
Agent: C#CC(C)CO
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)C#Cc1ccc2c(n1)-n1cc(C(N)=O)nc1CCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Into a 20-mL sealed tube was placed a solution of methyl 2-(3-hydroxy-3-methylbut-1-yn-1-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate (100 mg, 0.31 mmol, 1.00 equiv, prepared by reaction of methyl 2-chloro-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate with 2-methylbut-3-yn-ol similar to as described in General Procedure G. The crude mixture was reacted with NH3.H2O (2 mL, 37%) in 1,4-dioxane (4 mL) similar to as described in General Procedure M. The resulting solution was stirred overnight at 100° C., diluted with 10 mL of H2O, extracted with 3×50 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, silica gel; mobile phase, DCM/MeOH (100:1-10:1); Detector, UV 254 um. This resulted in 423 mg (44%) of the titled compound as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH2:15])=[O:14]>CS(C)=O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH2:15])=[O:14]
Reactant: NC(=O)CN1C(=O)C(=O)c2ccccc21
Solvent: CS(C)=O
Product: NC(=O)CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
The above 2-(2,3-dioxoindolin-1-yl)acetamide (4.32 g) was redissolved in DMSO (20 mL) and N2H4-xH2O (2.5 mL) was added dropwise over 10 min. After addition, the resulting mixture was stirred for 5 min at rt, then 2 h at 140° C. before cooling to rt. The reaction was quenched with ice (20 mL) and 6 M HCl (8 mL), then stirred for 30 min at rt. Suction filtration gave crude title compound (2.92 g) as a light yellow solid. The product was suspended in EtOAc (120 mL) and H2O (60 mL) was added, followed by 2 M HCl (30 mL). The mixture was separated and suction filtration of aqueous layer affored the title compound as a light beige solid (1.78 g, 27% over 2 steps) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H, NH), 7.28-7.08 (m, 4H), 6.99 (t, J=7.4 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 4.22 (s, 2H), 3.56 (s, 2H); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.1; MS ESI 174.0 [M−NH2]+, calcd for [C10H10N2O2—NH2]+ 174.1; MS ESI 146.0 [M−CONH2]+, calcd for [C10H10N2O2—CONH2]+ 146.1.