Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1cccc(N)c1
Agent: Cl
Product: COC(=O)Cc1cccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Yield: 83.5 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.160 g, 0.53 mmol) was reacted with methyl 2-(3-aminophenyl)acetate (0.130 g, 0.79 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.190 g, 91%) as a white solid. MW=429.34. 1H NMR (DMSO-d6, 500 MHz) δ 14.04 (s, 1H), 9.81 (s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.76-7.71 (m, 1H), 7.69-7.64 (m, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.38-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.23-7.17 (m, 1H), 7.09 (s, 1H), 3.77 (s, 2H), 3.62 (s, 3H), 3.16 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)[CH3:2].[C:12](Cl)(=[O:21])[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl[Sn]Cl.Cl>C1C=CC=CC=1.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[C:7]=1[C:12](=[O:21])[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCc1cc2ccccc2o1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: c1ccccc1
Solvent: O
Product: CCc1oc2ccccc2c1C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
--To an ice cooled solution of 2-ethyl benzofuran 5.0 g and 5.9 g of o-anisoyl chloride dissolved in 20 ml benzene were added 4.1 ml of SnCl2 dropwise; the reaction mixture was stirred for 3 hours at room temperature. Then it was poured into water,30 g, containing 5 ml of conc. HCl. The benzene layer was separated and the solution was extracted with benzene again. The combined benzene layer was washed with a 5% NaHCO3 solution and then with water. After drying and removal of benzene under reduced pressure, the yellowish oil, 2-ethyl-3-(o-anisoyl) benzofuran was obtained. Pyridine-HCl was prepared by the introduction of dried HCl gas to 4.75 g of pyridine and a 50 ml of benzene solution, and then by removing benzene twice.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[O:26]1CC[CH2:28][CH2:27]1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:27]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]=3[C:5]=2[N:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])(=[O:26])[CH3:28]
Reactant: On1c(-c2ccccc2Cl)nc2c3ccc4ccccc4c3ccc21
Reactant: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)On1c(-c2ccccc2Cl)nc2c3ccc4ccccc4c3ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4 parts of 1-hydroxy-2-(2-chlorophenyl)-phenanthroimidazole in 30 parts of tetrahydrofuran are initially taken, and 2 parts of pyridine and 3.6 parts of acetic anhydride are then added. Tne mixture is stirred for five hours at room temperature, after which 40 parts of ethyl acetate are added to the resulting solution. The organic phase thus obtained is washed several times with water and dried over sodium sulfate, after which the solvent is stripped off. The solid which remains is recrystallized from methyl ethyl ketone/cyclohexane.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22].Br[CH2:28][CH:29]1[CH2:31][C:30]1([F:33])[F:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:32][C:30]1([F:33])[CH2:31][CH:29]1[CH2:28][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([F:1])=[C:3]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:4]=[CH:5][C:6]=3[N:7]=2)=[CH:12][C:13]=1[F:18]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1F
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4(F)F)c(F)c3)oc2c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of N-((2S)-1-((7-fluoro-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (810 mg), 1-bromomethyl-2,2-difluorocyclopropane (573 mg) and potassium carbonate (463 mg) in DMF (10 mL) was stirred at 70° C. for 1 hr and 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was washed with diethyl ether to give the title compound (880 mg).
Reaction SMILES: Br[CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.CC(C)=[O:24]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:24][CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2O
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
Silver nitrate (0.3 g, 2.00 equiv) was added to a stirred solution of ethyl 4-bromo-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (400 mg, 0.86 mmol, 1.00 equiv) in acetone (20 mL)/water (20 mL) was added. The resulting mixture was stirred for 12 hours at room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:3) to give 0.12 g (35%) of the titled compound as a white solid. LC-MS (ES, m/z) 401[M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1

Procedure:
A solution of 5-benzyl-3-bromo-6-(1-bromopropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-3, 5.0 g, 11.7 mmol, 1 equiv) and N,N-dimethylethylenediamine (2.6 g, 29.3 mmol, 2.5 equiv) in ethanol (25 mL) was heated at reflux for 18 h. The reaction was concentrated, and the residue was purified by flash chromatography. Elution with CH2Cl2 to 25% NH3-EtOH/(CH2Cl2 gave 5-benzyl-3-bromo-6-(1-{[2-(dimethylamino)ethyl]amino}propyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-4) as a light green foam. 1H NMR (500 MHz, CDCl3) δ 11.1 (bs, 1H), 7.33 (m, 2H), 7.29 (m, 1H), 7.15 (d, J=7 Hz), 5.97 (d, J=16 Hz), 4.71 (d, J=16 Hz), 3.58 (m, 1H), 2.52 (m, 1H), 2.30 (m, 2H), 2.24 (s, 6H), 1.94 (m, 1H), 1.52 (m, 1H), 1.31 (m, 1H), 0.84 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[N:4][S:5]([C:8]1[S:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][N:2]([CH3:17])[CH:3]=[N:4][S:5]([C:8]1[S:16][C:11]2=[CH:12][N+:13]([O-:26])=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1cc2ccncc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C)C=NS(=O)(=O)c1cc2cc[n+]([O-])cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a solution of N,N-dimethyl-N'-(thieno[2,3-c]pyridine-2-sulfonyl)formamidine (2.05 g, 7.6 mmol) in chloroform (30 ml) was added dropwise a solution of m-chloroperbenzoic acid (1.82 g, 8.5 mmol) in ethyl acetate (17 ml). After stirring at room temperature for 18 hours, the precipitated product was collected on a filter. The filtrate was concentrated to obtain additional product. The combined material (2.08 g) was crystallized from chloroform to give 1.98 g (91% yield) of pure product; m.p. 237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:32]=3[F:31])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)c(F)c1
Yield: 29.3 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.200 g, 0.512 mmol), thionyl chloride (2.0 mL), 2-fluoro-4-methylaniline (0.128 g, 1.025 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 2.29 (s, 3H), 3.10 (s, 2H), 7.00 (d, J=8.1 Hz, 1H), 7.15 (d, J=12 Hz, 1H), 7.24 (m, 1H), 7.42 (m, 1H), 7.53 (d, J=8.1 Hz, 2H), 8.33 (t, J=8.4 Hz, 1H), 9.99 (s, 1H), 11.00 (s, 2H); MS [M+H]+: 500.39.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[S:11](Cl)(=[O:13])=[O:12].O>CO.O1CCCC1>[Br:2][C:3]1[C:4]2[S:11](=[O:13])(=[O:12])[N:10]=[C:9]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: N#Cc1cccc(Br)c1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NC1=NS(=O)(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.1 ml of ammonia in methanol (7M) is added at ambient temperature to a solution of 1.85 g of 2-bromo-6-cyano-benzenesulfonyl chloride in 40 ml of tetrahydrofurane. The reaction mixture is stirred for 16 hours at ambient temperature. Then the mixture is poured into water and extracted with ethylacetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue with cyclohexane—ethyl acetate (1:1) affords 730 mg of 7-bromo-1,1-dioxo-1H-1λ6-benzo[d]isothiazol-3-ylamine (P1.1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:11])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:35])[CH2:33][S:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: S=c1cc[nH]c2ccccc12
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CSc1ccnc2ccccc12)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Quinoline-4(1H)-thione (3.50 g, 21.9 mmol) and potassium carbonate (3.95 g, 28.5 mmol) were suspended in dry acetone(350 ml). 1-Benzyloxy-4-bromoacetylbenzene (8.00 g, 26.3 mmol) was gradually added to the suspension under ice cooling and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added with water, extracted with ethyl acetate, washed with saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed by silica gel column chromatography (n-hexane:ethyl acetate=1:4) and recrystallized from ethyl acetate to obtain 5.43 g of the titled compound (64.4%) as yellow-white crystal.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Reactant: COc1cc(C=O)cc(OC)c1
Product: CCCc1c(OC)cc(C=Cc2cc(OC)cc(OC)c2)cc1OC
Yield: 25 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 3,5-dimethoxybenzaldehyde in 25% yield as the same procedure as described in Example 5(b)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[C:7]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:21][C:18]([C:13]1[CH:14]=[C:15]([NH:17][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[O:6])[CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]=1[OH:22])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C=NCCCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)NCCCl)cc(C(C)(C)C)c1O
Temperature: 23 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
0.17 ml (2 mmol) of chloroethylisocyanate is added to a flask containing a solution of 0.5 g (2 mmol) of intermediate 10.2 in 5 ml of DMF. The reaction mixture is agitated for 2 hours at 23° C. and finally diluted with 100 ml of ethyl acetate and 25 ml of water. After decantation, the organic solution is washed with 25 ml of water, twice with 25 ml of salt water and finally dried over magnesium sulphate. After filtration and evaporation, the residue is taken up in isopentane in order to finally produce the expected product, in the form of a pink solid, with a yield of 83%. Melting point: 169-171° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:35]=2)[N:30](C(OC(C)(C)C)=O)[N:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(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].C(Cl)Cl.O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[C:28]3[CH3:27])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]nc(C)c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.12 g, 0.321 mmol), 1,1-dimethylethyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (0.138 g, 0.385 mmol), potassium phosphate (tribasic) (0.204 g, 0.963 mmol), 1,4-dioxane (3 mL), and water (0.75 mL). The stirring suspension was degassed with nitrogen for 10 min., wherein an emulsion had formed. Next added PdCl2(dppf)-CH2Cl2 adduct (0.039 g, 0.048 mmol) and the contents were placed onto a heat block and stirred at 105° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through Celite. The filter pad was washed with 50% THF/EtOAc. Silica gel was added to the combined filtrates and the mixture concentrated in vacuo to a solid. The contents were purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of DCM and chloroform containing 10% 2M Ammonia (in methanol)). The isolated solid was dried in vacuum oven at 45° C. overnight to afford the final product as 0.126 g (81%). LCMS E-S (M+H)=470.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.57 Hz, 6H), 2.13 (s, 3H), 2.25 (s, 3H), 2.60 (s, 3H), 4.43 (d, J=5.05 Hz, 2H), 5.31-5.43 (m, 1H), 5.91 (s, 1H), 7.60 (d, J=8.84 Hz, 1H), 8.22 (s, 1H), 8.29-8.37 (m, 2H), 8.60 (s, 1H), 8.97 (t, J=5.05 Hz, 1H), 11.58 (br. s., 1H), 12.84 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(C)CCN(C)C.C([N-]CC)C.[K+].[C:25](=[O:27])=[O:26]>C(N(CC)CC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:25]([OH:27])=[O:26]
Reactant: COc1cccc(OC)c1
Reactant: O=C=O
Agent: CC[N-]CC
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(OC)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of 1,3-dimethoxybenzene (12.06 g.) and tetramethylethylenediamine (15 ml.) in triethylamine (20 ml.) was added to the potassium diethylamide reaction mixture and stirred for two hours. The entire mixture, a gray suspension, was poured into a 1-liter beaker containing crushed dry ice (456 g.) with the aid of 35 ml of added triethylamine and was allowed to warm to room temperature. The contents of the beaker were transferred into a 1-liter flask with the aid of some water. All volatile components were removed by a rotary evaporator. The solid remaining in the flask was partitioned between diethyl ether (30 ml.) and water, which was extracted with diethyl ether (four times, 30 ml.). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1. The resultant precipitate was collected by filtration, water-washed and air dried to give 10.99 g. (69% yield) of 2,6-dimethoxybenzoic acid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH2:15][CH2:16][CH2:17][Cl:18])=[O:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(O)(=O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH:15]([Br:19])[CH2:16][CH2:17][Cl:18])=[O:14])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=C(CCCCl)c1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(c1ccc(-c2ccccc2)cc1)C(Br)CCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
246 g (0.95 mol) of 3-chloropropyl 4-phenylphenyl ketone in 380 ml of glacial acetic acid were placed in a reaction flask and 152 g (0.95 mol) of bromine were added dropwise at 30° C., the reaction commencing with dissolution and decolorization. After 1 hour, a thick precipitate deposited. The mixture was stirred for a further 4 hours at room temperature in order to complete the reaction. The crystals produced were filtered off under suction, washed with water, dissolved in dichloromethane, washed by shaking with NaHCO3 solution and water and dried, and 250 g (78% of theory) of the title substance were obtained as colorless crystals of melting point 85°-88° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[CH:6]=[C:7]3[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH2:16])=[CH:4][C:5]2[CH:6]=[C:7]3[C:13]([CH3:14])([CH3:15])[CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: CC1(C)CCn2c1cc1cc([N+](=O)[O-])c(F)cc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)CCn2c1cc1cc(N)c(F)cc12
Yield: 49.6 %

Procedure:
To a solution of 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole (600 mg, 2.4 mmol) in ethanol (15 mL) was added ammonium formate (600 mg, 9.5 mmol) and Pd/C (10%, 129 mg, 0.12 mmol). The mixture was refluxed for 10 min. The Pd catalyst was removed via filtration through Celite and washed with ethanol. The filtrate was concentrated and purified by column chromatography (20-40% ethyl acetate-hexanes) to provide 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (260 mg, 49%). ESI-MS m/z calc. 218.1, found 219.2 (M+1)+. Retention time 1.01 minutes.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH:36]([O:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:19][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:26]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)([CH3:38])[CH3:37]
Reactant: CC(C)Oc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cnc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 60 mg), 2-chloro-5-isopropoxy-pyrimidine (25 mg), potassium carbonate (45 mg), and N-methyl-pyrrolidinone (2 ml) is stirred in a microwave oven at 150° C. for 20 min. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:5:0→5:5:1) to give the title compound. LC (method 3): tR=0.93 min; Mass spectrum (ESI+): m/z=526 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][NH:36][CH2:35][C:34]([F:38])([F:37])[F:33])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: NCC(F)(F)F
Reactant: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncnn2c(CNCC(F)(F)F)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 36.4 %

Procedure:
To a suspension of N-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea (5.0 mg, 0.011 mmol) in 1,2-dichloroethane (2 mL) was added 2,2,2-trifluoroethylamine (11.2 mg, 0.11 mmol), followed by sodium triacetoxyborohydride (24.0 mg, 0.11 mg). The mixture was stirred at rt under nitrogen for 4 d. The solvent was evaporated under reduced pressure. The residue was dissolved in DMF and purified by HPLC using a gradient of 20-90% MeCN in water to yield 2.1 mg (35%) of the title compound. 1H-NMR (DMSO-d6) 9.95 (bs, 1 H), 9.79 (bs, 1 H), 8.05-7.99 (m, 2 H), 7.90 (s, 1 H), 7.57 (d, J=8.6, 2 H), 7.50 (dd, J=6.4, 1.7, Hz, 1 H), 7.40 (d, J=8.6 Hz, 2 H), 6.66 (s, 1 H), 4.07 (d, J=6.8 Hz, 2 H), 3.30-3.23 (m, 2 H), 2.92-2.85 (m, 1 H); MS [M+H]+=525.1; LCMS RT=2.91 min.