Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:15][C:14]=3[F:35])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].CS(O[CH2:43][CH2:44][CH2:45][C:46]1([OH:49])[CH2:48][CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:49][C:46]1([CH2:45][CH2:44][CH2:43][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:23][CH2:24]5)=[O:21])=[CH:15][C:14]=4[F:35])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:36][CH3:37])[CH2:48][CH2:47]1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCC1(O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (300 mg, 0.594 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155 mg, 0.80 mmol), and Cs2CO3 (581 mg, 1.782 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (6:1 (v/v) EtOAc/n-hexane). The title compound was obtained as a white solid (247 mg, 69%).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]1([CH:7]2[O:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1COC(c2ccccc2)OC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1COC(c2ccccc2)OC1
Yield: 26.3 %

Procedure:
To a solution of (2-phenyl-1,3-dioxan-5-yl)methanol (2.0 g) in dichloromethane (40 ml) were added pyridinium chlorochromate (11.6 g) and molecular seaves 4A powder (5.0 g) with stirring and the mixture was stirred at ambient temperature for 5 hours. To a reaction mixture was added dichloromethane (100 ml) and the insoluble material was filtered off with celite and the filtrates were washed in turn with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give 2-phenyl-1,3-dioxane-5-carbaldehyde (0.52 g). This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([OH:20])=O.[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:22][CH3:21])=[O:20]
Reactant: O=C(O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a stirred solution of compound (xvi) (50 mg, 0.15 mmol) in DMF (5 mL) were added HATU (85 mg, 0.22 mmol) DIPEA (0.1 mL, 0.45 mmol) and methyl amine solution (0.26 mL, 0.15 mmol) at 0° C. and the reaction mixture was stirred at RT. After 12 h the reaction mixture was diluted with water and the precipitated solid was filtered to give 6-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (xvii) (30 mg, 58%) as a white solid. ESI-MS m/z calculated for [M+H]+: 348.01; found: 347.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14](OCC)=[O:15])=[C:9]2[C:19](OCC)=[O:20])=[CH:5][CH:4]=1.O.[NH2:27][NH2:28]>COCCOCCOC>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:9]3[C:19](=[O:20])[NH:27][NH:28][C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH3:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(C)n(Cc2ccc(OC)cc2)c1C(=O)OCC
Reactant: NN
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(Cn2c(C)cc3c(=O)[nH][nH]c(=O)c32)cc1
Yield: 87 %

Procedure:
46.0 g (0.133 mol) of diethyl 1-(4-methoxybenzyl)-5-methylpyrrole-2,3-dicarboxylate and 129.5 ml (2.66 mol) of hydrazine hydrate are reacted at 110° C. for 18 h in 290 ml of diglyme. Purification: precipitation from diisopropyl ether/ethyl acetate. Yield: 87%, m.p.: 300° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[O:12][CH2:13][CH2:14][NH:15][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1>[O:12]1[CH2:13][CH2:14][NH:15][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]1=2
Reactant: CCOC(=O)c1cccc2c1OCCN2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c1OCCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid ethyl ester 2.1 g (10 mmol) of step 3 in a mixture of tetrahydrofuran 10 mL and distilled water 10 mL was added lithium hydroxide monohydrate 0.85 g (20 mmol), followed by stirring at room temperature for 8 hrs. After concentrating the reaction mixture in a vacuum, the reaction mixture was diluted with ethylacetate, washed with 1N HCl and a saturated NaCl solution, and dried over magnesium sulfate. The residue was concentrated in a vacuum and crystallized in ethylacetate/hexane to obtain 1.6 g of the title compound (yield 89%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1[C:18]2[NH:17]C3C(=CC=CC=3)SC=2C=C[CH:6]=1.[C:19](O)([CH3:22])([CH3:21])[CH3:20].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[C:1](#[N:4])[CH:2]=[CH2:3].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:19]([NH:17][C:18](=[O:27])[CH:5]=[CH2:6])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O=C(O)C(F)(F)F
Solvent: C=CC#N
Product: C=CC(=O)NC(C)(C)C
Reaction time: 6 h

Procedure:
84 g of acrylonitrile are added dropwise to a solution of 1 g of phenothiazine in 90 g of trifluoroacetic acid at 20° C., whilst stirring. Thereafter, 43 g of tert.-butanol are added dropwise at 35° C. The reaction mixture is kept at 60° to 70° C. for 6 hours and then worked up by distillation. Acrylonitrile, trifluoroacetic acid and some of the N-tert.-butylacrylamide formed are distilled off under reduced pressure. 36 g of N-tert.-butylacrylamide (melting point 120° to 122° C.) remain as the distillation bottom product. The distillate can be re-used in the reaction with the same result.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[Br:51]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:51][C:5]1[C:6]2[CH2:23][C@@H:22]([OH:24])[C@:21]3([O:25][CH3:26])[C@:8]([OH:45])([C:7]=2[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]=1[CH3:46])[C:9](=[O:44])[C:10]1[C:19](=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=1)[C:20]3=[O:27]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C)c(Br)c2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 75 °C
Yield: 35.8 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (50 mg, 0.072 mmol) in chloroform (1 mL) was added N-bromosuccinimide (13 mg, 0.072 mmol) followed by benzoyl peroxide (1-2 mg). The reaction mixture was refluxed at 75° C. for 1 h. After cooled to room temperature, the reaction mixture was diluted with chloroform (10 mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous layer was further extracted with chloroform (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) and semi-preparative HPLC to afford (6R,6aS,14aR)-methyl 4-bromo-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (20 mg, 36%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.22 (s, 1H), 11.62 (br s, 1H), 8.19 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.88 (s, 1H), 5.29 (s, 1H), 4.99 (s, 1H), 4.72 (s, 1H), 4.68 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.55 (d, J=6.5 Hz, 1H), 3.45 (d, J=20.5 Hz, 1H), 3.41 (s, 3H), 3.38-3.31 (m, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.59 (s, 3H), 2.48 (d, J=4.5 Hz, 1H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 776 (M+H); HPLC >99% (AUC), tR 14.64 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Br:39]C1C=CC=CC=1CC(=O)C(OCC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Br:39])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccccc1Br
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1ccccc1Br)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 17 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(2-bromophenyl)-2-oxopropanoate B8 (100 mg, 0.369 mmol), sodium hydride (9.74 mg, 0.406 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-glucose bromide (152 mg, 0.369 mmol). The resulting compound was isolated in the form of white solid in 17% yield.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][N:7]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(CC(=O)O)nc1
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CC(=O)Nc2ccc(C)c(C)c2)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77.9 %

Procedure:
To a 0° C. solution of 400 mg (2.12 mmol) (5-methyl-pyridin-2-yl)-acetic acid hydrochloride (CAS: 848093-05-0) in 7.5 mL dichloromethane were added successively 250 mg (2.02 mmol) 3,4-dimethylaniline and 415.4 mg (2.12 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 45 minutes. The solution was washed with a sat. NaHCO3 solution, NaOH 2N and with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.40 g (77%) of the title compound as an off-white solid. MS (m/e): 255.2 [M+H]+.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.[C:20](=O)([O-])[OH:21].[Na+]>CN(C=O)C.C(OCC)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH:20]=[O:21])=[CH:18][N:17]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1ccc(Cl)nc1

Procedure:
At −78° C., a hexane solution (11.5 mL) of 1.59 M n-butyllithium was dropwise added to a diethyl ether solution (140 mL) of 5-bromo-2-chloropyridine (2.9 g). This was stirred at that temperature, then a diethyl ether solution (3 mL) of DMF (1.8 mL) was added thereto and stirred at that temperature for 3.5 hours. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/9) to obtain the entitled compound (1.4 g).
Reaction SMILES: [Na].[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:5]=1.[CH3:26][O:27]CCO>>[CH3:26][O:27][CH2:23][CH2:22][O:21][C:19]([C:18]1[CH:17]=[N:16][N:15]2[C:10]([C:6]3[CH:5]=[C:4]([C:3]([F:24])([F:2])[F:25])[CH:9]=[CH:8][CH:7]=3)=[CH:11][CH:12]=[N:13][C:14]=12)=[O:20]
Reactant: COCCO
Reactant: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [Na]
Product: COCCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
One hundred milligrams of metallic sodium is added to 50 ml. of 2-methoxyethanol and after it has dissolved, 3.35 g. of ethyl 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate is added and the mixture is refluxed for one hour. On cooling, the desired compound crystallizes from the solution and is removed by filtration. Recrystallization from methylene chloride-hexane affords the product as crystals, m.p. 111°-112° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>O>[ClH:11].[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[CH:4]([OH:13])[CH2:3][NH:2][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: COc1cccc(C=O)c1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(CNCC(O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
The free base obtained from 70.0 g. of rac.-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is heated at reflux in 1 l. of benzene with 40.8 g. of 3-methoxybenzaldehyde using a water-separator for 2 hours until no more water is released. After concentration and dissolving in 1 l. of methanol, the product is reduced with 30 g. of sodium borohydride below 5°, evaporated and extracted with methylene chloride and water. The methylene chloride extract, acidified with ethanolic hydrogen chloride, crystallizes with ethyl acetate and, after recrystallization from methanol-ether, yields rac.-3,4-dichloro-α-{[(3-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride, m.p. 198°-200°. The free base recrystallized from methanol-petroleum ether has a m.p. of 94°-95°.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12](#[N:16])[CH:13]([CH3:15])[CH3:14].C[Si](C)(C)[N-][Si](C)(C)C.[K+].B.C1COCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:13]([CH3:15])([CH3:14])[C:12]#[N:16])=[N:4][CH:5]=[C:6]([CH2:7][OH:9])[CH:10]=1
Reactant: CC(C)C#N
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: B
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ncc(CO)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a magnetically stirring solution of 5,6 dichloronicotinic acid (2.7 g, 14.06 mmol) in THF (70.0 mL), was added isobutyronitrile (6.37 mL, 69.66 mmol) followed by potassium hexamethyldisilazide 0.5 M in toluene (70 mL). The resulting orange mixture was stirred at 60° C. overnight. Solvents were removed and residue portioned between ethyl acetate (100 mL) and 1N HCl (100 mL). The layers of the resulting reaction mixture were separated and the aqueous layer was extracted three additional times with ethyl acetate. The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo to a yellow solid (3.34 g). This crude residue was dissolved in THF (80 mL) and reaction cooled to 0° C. BH3.THF 1 M solution in THF (22.30 mL) was added and reaction stirred at 0° C. for 4 hours, then room temperature overnight. Solid K2CO3 (2 g) and water (100 mL) were added and the aqueous layer was extracted three additional times with ethyl acetate. The organics were combined dried over Na2SO4, filtered and concentrated in vacuo to a clear oil which was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.95 g, 32%). ESIMS (MH+): 210.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:32])[C:24]4[C:29]([CH:30]=3)=[C:28]([CH3:31])[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1.CCOC(C)=O>[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:32])[C:24]4[C:29]([CH:30]=3)=[C:28]([CH3:31])[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(N4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)nc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(N4CCN(CCO)CC4)nc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To a solution of 3-(6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-yl}-pyridin-3-yl)-5-methyl-2H-isoquinolin-1-one (214 mg, 0.45 mmol) in THF (1.5 mL) at 5° C. was added 1M TBAF/THF (0.58 mL, 0.58 mmol) dropwise. The reaction mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water and brine. The organic layer was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain 3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-3-yl}-5-methyl-2H-isoquinolin-1-one as a yellow solid (27 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH3:27]OC(C1C=C(OC2C=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC(C)(C)OC=2C=1)=O.C(N)C>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH2:25][CH3:27])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2
Agent: CCN
Product: CCNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid 66a) (74 mg, 0.22 mmol) and ethyl amine (2.0 M in THF, 1 mL) to give a white solid (28 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=2.78 Hz, 1 H) 8.18 (d, J=8.59 Hz, 1 H) 7.82-7.91 (m, 1 H) 7.34 (dd, J=8.59, 2.78 Hz, 1 H) 7.25 (s, 1 H) 7.19 (d, J=1.01 Hz, 1 H) 3.87 (s, 3 H) 3.52 (dd, J=7.33, 6.06 Hz, 2 H) 2.90 (s, 2 H) 1.49 (s, 6 H) 1.22-1.33 (m, 3 H); LCMS for C20H22N2O5 m/z 371.00 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.CO>[N:15]1([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.0 g (9.28 mmol) product from Step A and 1.6 mL (18.6 mmol) morpholine in 20 mL DMF was heated to 90° C. for 6 hours. After the mixture had cooled to room temperature, the DMF was stripped off in vacuo. The crude material was then redissolved in methanol and stirred with 20 g Amberlyst-A26® for about 20 minutes. The mixture was then stripped of solvent and used without further purification in the next step. Rf 0.20 in 40% EtOAc/hexane, visualized by UV and visible light.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[CH:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1nc(-c2ccccc2)sc1C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1nc(-c2ccccc2)sc1C=CC(=O)O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 300 mg (1.47 mmol) of 4-methyl-2-phenyl-thiazole-5-carbaldehyde, 169 mg (1.62 mmol) of malonic acid and 880 mg (10.33 mmol) of piperidine in 10 ml of pyridine was stirred at 90° C. for 5 h and at 100° C. for 6 h. After concentration, the residue was treated with a sodium hydrogencarbonate solution and ethyl acetate. The aqueous phase was separated and acidified. The precipitated product was filtered off with suction and dried. Yield: 260 mg.
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:7]1)=[O:5]>[Hg]>[CH3:1][C:2]1([CH3:24])[C:13]2[C:12]3=[C:11]([CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:7][N:6]3[C:4](=[O:5])[CH2:3]1)[CH:16]=[CH:15][CH:14]=2
Reactant: CC(C)=CC(=O)N1CCN(C(=O)OC(C)(C)C)Cc2ccccc21
Agent: [Hg]
Product: CC(C)(C)OC(=O)N1CCN2C(=O)CC(C)(C)c3cccc(c32)C1
Yield: 61.1 %

Procedure:
A solution of 0.33 g (1.0 mmol) of tert-butyl 1-(3-methylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate of step 1.1 was irradiated with a 150 W mercury lamp in a immersion well reactor with a pyrex filter in 20 mL of acetone until completion of the reaction monitored by liquid chromatography. The solution was concentrated in vacuo and the residue was purified by column chromatography on silica (eluent: 10-30% ethyl acetate in heptane) to yield 202 mg of the title compound as a beige solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:11]([CH:13]2[CH2:16][N:15]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=O)[CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[N:7]1([CH2:11][CH:13]2[CH2:14][N:15]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16]2)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C(C1CN(C(c2ccccc2)c2ccccc2)C1)N1CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)N2CC(CN3CCC3)C2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
Lithium aluminium hydride (300 mg) was suspended in tetrahydrofuran (10 ml) at room temperature under a nitrogen atmosphere, and a solution of 3-(azetidin-1-ylcarbonyl)-1-benzhydrylazetidine (1.14 g) in tetrahydrofuran (30 ml) was added dropwise. After the addition, the reaction mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled in an ice water bath, water (0.3 ml), a 5N aqueous solution of sodium hydroxide (0.3 ml) and water (0.9 ml) were added, followed by stirring overnight. Insoluble matter was removed by filtration, and washed with ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure to give the title compound (1.115 g, quant.) as a pale brown oil.