Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19]C(=O)OC(C)(C)C)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH2:19])[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl(S)-1-(2-(3,5-dichlorophenylamino)acetyl)piperidin-3-ylcarbamate (0.9 mg, 2.2 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in dioxane (10 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the resultant residue was dissolved in water and aqueous phase was adjusted to a pH 9 with sat. NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na2SO4 and evaporated in vacuo to afford the titled intermediate (540 mg, 79%), which was used in the next step without purification. LCMS: m/z: [M+1]=302.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>CC(N(C)C)=O.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]>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[N:13]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 75 °C
Yield: 77.9 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.17 g, 5.55 mmol) and Pd(dppf)Cl2 (37 mg, 0.045 mmol) were placed in a N2 purged round-bottom flask. The reagents were dissolved in DMA (6 ml) and purged with N2. An aqueous solution of K2CO3 (978 mg in 6 ml) was then added slowly to the reaction mixture, while maintaining the temperature below 40° C., and purged for 10 minutes with N2. The solution was then heated to 75° C. overnight. Heating was discontinued and 12 ml of H2O was added. The solution was then heated to 60° C. for 1 h. Next, the solution was transferred to a separatory funnel and extracted with dichloromethane (100 ml×2). The organic layer was dried over Na2SO4 and concentrated down onto silica gel. The reaction mixture was purified by flash chromatography using a gradient of 0-10% methanol/di-chloromethane to afford 780 mg of 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (78% yield): 1H NMR (DMSO-d6) δ 3.94 (3H, s), 6.49 (1H, d), 7.38 (1H, d), 7.84 (1H, s), 7.97 (1H, s), 8.12 (1H, d), 8.38 (1H, d); MS (m/z) 199 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19](O)=[O:20])[CH:15]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:15]=[C:14]([CH3:13])[O:18][N:17]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 5-methylisoxazole-3-carboxylic acid (221 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol). The mixture was stirred at room temperature overnight and additional BOP-Cl (81 mg, 0.87 mmol) and 5-methylisoxazole-3-carboxylic acid (110 mg, 0.87 mmol) were added. The mixture was stirred for an additional 48 hours at room temperature. Next, 2M LiOH (3 mL) was added to the mixture and stirred for 1 hour. The organic solvent was removed in vacuo, and water:CH2Cl2 (11 mL; 10:1) were added to the aqueous residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide (210 mg, 71% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.12 (s, 1H), 10.22 (s, 1H), 8.33 9d, 1H), 7.58 (s, 1H), 2.45 (s, 3H); LCMS (APCI+) m/z 338.9, 340.9 (M+H)+, Retention time=3.16 minutes (Method 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24]C4N(N=C(C5N(CC(F)(F)F)N=CN=5)C=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2OCC[C:48]3[C:44](=[N:45][N:46]([C:52]4[N:53]([C:57]5[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=5[F:64])[N:54]=[CH:55][N:56]=4)[CH:47]=3)C=2C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:48]4[C:44](=[N:45][N:46]([C:52]5[N:53]([C:57]6[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=6[F:64])[N:54]=[CH:55][N:56]=5)[CH:47]=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(Br)ccc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Yield: 77 %

Procedure:
4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared similarly to 4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from 9-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.55 mg, 1.13 mmol) to give the title compound as a colourless gum (1.47 g, 77%). LCMS RT=5.01 min, M+H+=547
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)=[O:9]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(NC(=O)c2cc(C)ccc2O)cc1C(F)(F)F
Yield: 65.1 %

Procedure:
Using 5-methylsalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([O:10]C)[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[CH:20]=3)=[C:14]([CH3:32])[N:13]=2)=[CH:6][N:5]=1)[CH3:2].Br>>[CH2:1]([NH:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[CH:20]=3)=[C:14]([CH3:32])[N:13]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(-c4ccc(C)nc4)c3)c(C)n2)c(OC)n1
Agent: Br
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4ccc(C)nc4)c3)c(C)n2)c(=O)[nH]1
Yield: 72.4 %

Procedure:
Using the procedure of Example 1, N-ethyl-4-methoxy-5-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.13 g, 0.3 mmol) and 48% HBr (0.66 mL, 12 mmol) were combined to afford 2-(ethylamino)-5-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one as a white solid (0.09 g, 73%). 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.53 (d, J=5.7 Hz, 1H), 8.28 (d, J=8.3 Hz, 2H), 7.62 (s, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 6.82 (br s, 1H), 6.78 (d, J=5.7 Hz, 1H), 3.35-3.32 (m, 2H), 2.50 (s, 3H), 2.35 (s, 3H), 1.12 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 415.2 (M+H+).
Reaction SMILES: FC1C=CC([CH2:6][N:7]2CCN3C=C(C(OCC)=O)C(O)=C3C2=O)=CC=1.[Cl:25][C:26]1[CH:48]=[CH:47][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]3[CH:37]=[C:38]([C:41]([O:43]CC)=O)[C:39]([OH:40])=[C:33]3[C:32]2=[O:46])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:48]=[CH:47][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]3[CH:37]=[C:38]([C:41]([NH:7][CH3:6])=[O:43])[C:39]([OH:40])=[C:33]3[C:32]2=[O:46])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)cc1)CC2
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)cc1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(4-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate (Example 13).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].C(Cl)Cl.[OH-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:10]([C:4]2[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=2[Br:2])[N:11]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: NNc1c(Cl)cccc1Br
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cnn(-c2c(Cl)cccc2Br)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
(2-Bromo-6-chlorophenyl)hydrazine hydrochloride (Intermediate AH2) (4.71 g, 18.26 mmol) was partitioned between DCM (300 mL) and 2M NaOH (20 mL). Allowed to Stir for 1 hour. The two phases were separated. The organic phase was reduced under vacuum to give the free base. This was dissolved in MeOH (60 mL), and stirred in a cooling bath at 0° C. (Ethoxymethylene)malononitrile (2.230 g, 18.26 mmol) added portionwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 1 hour. The mixture was then heated to reflux and stirred for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated to give a solid, which was triturated under MeOH. A solid was filtered off. This was dried to afford the product (4.59 g, 85%). 1H NMR (400 MHz, DMSO) δ 6.79 (2H, s), 7.54-7.47 (1H, m), 7.70 (1H, dd), 7.79 (1H, s), 7.81 (1H, d). m/z (ES+) (M+H)+=299; HPLC tR=1.70 min.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([NH2:25])[N:22]3[N:26]=[CH:27][C:28]([C:29]4[CH:30]=[N:31][C:32]5[C:37]([CH:38]=4)=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:21]3[N:20]=2)[CH2:15][CH2:14]1>CN(C=O)C.[NH4+].[Cl-]>[O:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([NH:25][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[N:22]3[N:26]=[CH:27][C:28]([C:29]4[CH:30]=[N:31][C:32]5[C:37]([CH:38]=4)=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:21]3[N:20]=2)[CH2:17][CH2:18]1
Reactant: Nc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CC(C)(C)OC(=O)CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C

Procedure:
NaH (25.1 mg, 60%, 0.63 mmol) and then tert-butyl 3-bromopropanoate (69.7 uL, 0.42 mmoL) was added to 5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (72.3 mg, 0.21 mmoL) in DMF (3 mL). The mixture was stirred at room temperature until LCMS indicated complete conversion. The reaction mixture was diluted with Sat. NH4Cl and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude tert-butyl 3-(5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoate. The crude ester was heated with 4N HCl (4 mL) and 1,4-dioxane (4 mL) at 50° C. for 3 h. Concentration provided 3-(5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoic acid. LCMS tR=1.10 Min (5 min run, UV254nm). Mass calculated for, M+ 418.1, observed LC/MS m/z 419.2 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23](=O)[NH:24][C:25]3[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=3[C:32](=[O:34])[NH2:33])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>O=S(Cl)Cl>[Br:31][C:29]1[CH:30]=[C:25]2[C:26]([C:32](=[O:34])[NH:33][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16]([O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[O:17])=[N:24]2)=[CH:27][CH:28]=1
Reactant: NC(=O)c1ccc(Br)cc1NC(=O)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=S(Cl)Cl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC1c1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 0 °C
Yield: 31.3 %

Procedure:
A solution of (9H-fluoren-9-yl)methyl-2-(5-bromo-2-carbamoylphenylcarbamoyl)pyrrolidine-1-carboxylate (0.55 g, 0.94 mmol) in excess SOCl2 was stirred at room temperature. After pouring into ice water, the mixture was adjusted to pH 7.0, extracted with ethyl acetate (3×100 mL) and concentrated to give the crude product. 152 mg of the desired product was obtained by column chromatography. MS (ESI): 516, 518 (MH+)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([NH:14]O)=[NH:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C.[Pd]>[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:16])[C:12]([NH2:14])=[NH:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=N)NO)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(C(C)C(=N)N)cc1
Yield: 90.9 %

Procedure:
2-(4-isobutylphenyl)-N-hydroxy-propionamidine (0.097 g, 0.44 mmol) is dissolved in acetic acid (3 mL) and treated at r.t. with acetic anhydride (0.06 mL, 0.66 mmol). 10% Pd on activated charcoal (0.03 g) is added and H2 is bubbled into the flask until the complete disappearance of the starting reagent. Methyl alcohol (5 mL) is added, the catalyst filtered off on a Celite cake and the solvents evaporated under reduced pressure to give an oily residue. Crystallisation of the crude residue from n-hexane gives 2-(4-isobutylphenyl)propionamidine acetate salt as white solid (0.106 g, 0.4 mmol). Yield 91%. m.p. >220° C. 1H-NMR (DMSO-d6): δ 8.70-8.50 (bs, NH3++NH); 7.42 (d, 2H, J=7 Hz); 7.23 (d, 2H, J=7 Hz); 3.85 (q, 1H, J=8 Hz); 2.52 (d, 2H, J=8 Hz); 1.97 (m, 1H); 1.75 (s, 3H); 1.60 (d, 3H, J=8 Hz); 0.95 (d, 6H, J=8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
4-Hydroxyphenylacetic acid (50.0 g) is dissolved in ethanol (400 ml) and thereto is added conc. sulfuric acid (0.5 ml). The mixture is refluxed with stirring, and ethanol is distilled off to give ethyl 4-hydroxyphenylacetate (60 g).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[S:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Yield: 75 %

Procedure:
The title compound was prepared from the product from step 4 (0.74 g, 2.5 mmol) and BBr3 (1M in CH2Cl2, 7.5 mL, 7.5 mmol) using the Step 2 procedure with 75% yield (0.5 g). 1HNMR (400 MHz, CDCl3) δ 6.78 (d, J=8 Hz, 1H), 6.84 (m, 3H), 6.95 (m, 4H), 7.29 (d, J=3.6 Hz, 1H), 7.83 (d, J=3.6 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]([O:13]/[N:14]=[C:15](/[CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)\[NH2:16])=O)[NH:8][C:5]2=[N:6][CH:7]=1.O>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:36][CH2:37][CH2:38]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[O:13][N:14]=[C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[N:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(C(=O)O/N=C(\N)C5CCN(C(=O)OC(C)(C)C)CC5)cc34)s2)CCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5nc(C6CCN(C(=O)OC(C)(C)C)CC6)no5)cc34)s2)CCC1
Temperature: 25 °C

Procedure:
A solution of Example 46D (0.66 g, 0.107 mmol) in 1-methyl-2-pyrrolidinone (1.2 mL) was heated at 110° C. for 5 hours. The reaction was cooled to ambient temperature and poured into water (5 mL). The resulting suspension was filtered, and the solid collected was washed with water and dried under vacuum to provide the title compound. MS ESI(+) m/z 601.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1C(O)=O>C1(C)C=CC=CC=1>[N:13]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: O=C(O)C1CCCCN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCCCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 13 g (0.1 mol) of piperidine-2-carboxylic acid in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH3:12])[NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1.C(O[C:17](=N)[C@@H:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:19])C>CCO>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:18]([C:17]1[N:7]2[C:6]3[C:11]([O:10][CH2:9][C@@H:8]2[CH3:12])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:13]=1)[CH3:19])([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@H]1COc2c(F)ccc(N)c2N1
Reactant: CCOC(=N)[C@H](C)NC(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 75 °C
Yield: 76.3 %

Procedure:
(S)-8-Fluoro-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine (160 mg, 0.86 mmol) was added to a solution of (S)-2-tert-butoxycarbonylaminopropionimidic acid ethyl ester (570 mg, 2.64 mmol) in EtOH (10 mL) and the reaction was heated at 75° C. for 60 min. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and sat. NaHCO3. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-40% DCM in cyclohexane) to afford the title compound as an off-white foam (220 mg, 76%). LCMS (Method J): RT=2.50 min, [M+H]+=336.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]4[C:21]([CH:22]=3)=[N:20][N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=4)[CH:9]=[C:10]([CH2:11][CH2:12]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C1COCC1>[CH2:23]([N:19]1[CH:18]=[C:17]2[C:21]([CH:22]=[C:14]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][Br:31])[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:15]=[CH:16]2)=[N:20]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(CCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of 2-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-ethanol (210 mg, 0.55 mmol) in anhydrous THF (5.5 mL) at 0° C. was added carbon tetrabromide (235.5 mg, 0.71 mmol, 1.3 eq) and triphenylphosphine (157.6 mg, 0.60 mmol, 1.1 eq), and the reaction mixture was stirred at rt for 16 h. The reaction was poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by MPLC (Biotage®) eluted with 15% acetone/DCM to give 222.6 mg (91%) of desired product as a white solid. 1H-NMR (300 MHz, DMSO-d6) 8.55 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.58 (s, 1H), 7.36 to 7.15 (m, 5H), 7.13 (d, 1H), 6.73 (s, 1H), 5.65 (s, 2H), 3.82 (t, 2H), 3.46 (t, 2H); ES-MS m/z 447.3/449.2 [M+H]+, RT (min) 2.91.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[CH3:12]>CO.[H][H].[Ni]>[CH3:1][N:2]([CH3:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: Cc1c(N(C)C)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1c(N)cccc1N(C)C
Yield: 93.7 %

Procedure:
73 g of N,N-dimethyl-2-methyl-3-nitroaniline are dissolved in 800 ml of methanol and hydrogenated at 20° C under 5 bar of hydrogen using Raney nickel as catalyst. 57 g of 3-dimethylamino-2-methylaniline are obtained.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N+]=[N-]>C1(C)C=CC=CC=1>[CH:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13]1[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:1][C:4]=1[C:5](=[O:20])[NH:6]2
Reactant: [N-]=[N+]=Nc1c(-c2ccccc2)c2ccccc2[nH]c1=O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2c2c1[nH]c1ccccc12

Procedure:
A suspension of 114 g. of 3-azido-4-phenylcarbostyril in 2 l. of toluene was heated to reflux until nitrogen evolution ceased (5 hours). On cooling, 7H-indolo[2,3-c]quinolin-6(5H)-one crystallized; 84.7 g. (84 percent), having a melting point of 314°-316° .
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH2:13]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C1COCC1>[CH2:13]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:1]1[SH:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Sc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
1,1′-Thiocarbonyldiimidazole (5.74 g, 32.2 mmol) was added to a solution of N4-benzylquinoline-3,4-diamine, see U.S. Pat. No. 4,689,338 (Gerster), Example 124, Parts A and B, (6.69 g, 26.8 mmol) in pyridine (50 mL) and THF (50 mL), and the reaction was heated at 80° C. for two hours and cooled to room temperature. A precipitate was present and was isolated by filtration and washed with diethyl ether to provide 4.17 g of 1-benzyl-1H-imidazo[4,5-c]quinoline-2-thiol as a white solid. The filtrate was treated with diethyl ether, and additional precipitate formed. The precipitate was isolated by filtration and washed with diethyl ether to provide an additional 1.90 g of product as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15]CCC[CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2.N1N2C(N=C3C(=C2O)C[O:23]C3)=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:3]2[C:7](=[CH:6][CH:5]=[N:4]2)[N:8]=[C:9]2[C:10]=1[CH2:11][O:23][CH2:15]2
Reactant: Oc1c2c(nc3ccnn13)COC2
Reactant: Clc1c2c(nc3ccnn13)CCCCC2
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3ccnn13)COC2

Procedure:
Using the method described for the preparation of 10-chloro-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 5H,7H-6-Oxa-1,4,8a-triaza-s-indacen-8-ol and phosphorus oxychloride provided the title compound.