Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:26][CH:25]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2c(C)c([N+](=O)[O-])cc3nc(OC)c(OC)nc23)cc1
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and 4-anisidine 207 mg (1.68 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 210 mg (66%), mp 206-208° C.; 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.71 (d, 2H, J=9.0 Hz), 7.60 (s, 1H), 6.88 (d, 2H, J=8.8 Hz), 4.16 (s, 3H), 4.00 (s, 3H), 3.79 (s, 3H), 2.57 (s, 3H); MS (APCI): m/z 399 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:13][CH3:14].O=S(Cl)Cl.[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CCCCCC>CCOC(C)=O>[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:9](=[O:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)[CH3:12]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1cc(C(C)C(=O)O)ccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1NC(=O)C(C)c1ccc(O)c(OC)c1
Yield: 83.7 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-hydroxy-3-methoxy-phenyl)-propionic acid (1.08 g, 5.50 mmol), SOCl2 (1.20 mL, 16.6 mmol), and 2-amino-benzoic acid methyl ester (0.56 g, 3.7 mmol). After normal workup, the pure objective compound (1.02 g, 56%) was obtained as pale yellow syrup by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.57 (d, J=7.32 Hz, 3H, CH3), 3.72 (q, J=7.32 Hz, 1H, CH), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, COOCH3), 5.73 (br s, 1H, ArOH), 6.89-7.05 (m, 4H, ArH), 7.45 (t, J=8.55 Hz, 1H, ArH), 7.94 (d, J=7.73 Hz, 1H, ArH), 8.67 (d, J=8.55 Hz, 1H, ArH), 11.07 (br s, 1H, NH).
Reaction SMILES: [I-].[Na+].[C:3](=[O:6])(O)[O-].[Na+].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27](CCl)[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O.[Cl-].[Na+].O>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27]([CH:3]=[O:6])[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nc(CCl)co2)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2nc(C=O)co2)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A 6.81 g quantity of sodium iodide and 5.09 g of sodium bicarbonate were added to a suspension of 10 g of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained in Reference Example 5 in 60 ml of dimethylsulfoxide. The mixture was heated at 120° C. with stirring for 30 minutes. After the reaction mixture was allowed to cool, saturated brine was added and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 2.98 g of yellow oily 2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][OH:23])=[O:9])([CH3:6])[CH3:5].[CH2:25]1[C:33]2[C:28](=[CH:29][C:30](O)=[CH:31][CH:32]=2)[CH2:27][CH2:26]1.CCOC(/N=N/C(OCC)=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[CH2:25]1[C:33]2[C:28](=[CH:29][C:30]([O:23][CH2:22][CH2:21][O:20][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][C:10]=3[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:2])=[O:24])=[O:9])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccc2c(c1)CCC2)C(=O)O

Procedure:
Under inert atmosphere to 166 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester, 74 mg indan-5-ol and 208 mg polystyrene-bound triphenyl phosphine (3 mmol/g) in 5 ml THF at 0° C. 98 μl diethylazodicarboxylate were added. After 16 h at room temperature the reaction was filtrated, the filtrate concentrated in vacuo and after RP-HPLC the obtained 2-({1-[2-(Indan-5-yloxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester was dissolved in 3 ml of dioxane and reacted with 3 ml 1N NaOH for 5 h at 50° C. The reaction was then diluted with ethyl acetate and treated with citric acid (5%). The organic layer was separated, dried and concentrated in vacuo. After purification by RP-HPLC 22 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11]([OH:13])=O)=[O:5])[CH3:2].Cl.Cl.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[CH2:29][CH2:30][NH2:31]>>[CH3:14][N:9]1[C:10]([C:11](=[O:13])[NH:31][CH2:30][CH2:29][C:19]2[N:18]([CH3:17])[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]=2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C

Procedure:
The product was obtained starting from 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.01 mmol, prepared as described in US 2011/0071128) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine hydrochloride (288 mg, 1.21 mmol, example 7, step 4) according to the method described in example 37, step 1 as light yellow solid (252 mg, 661 μmol, 65.5%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH:27]([N:34]=[C:35]=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:27]([NH:34][C:35]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:5]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:16][CH2:17]1)=[O:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(CN2CCNCC2)(c2ccccc2)CC1
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of 1-((methyl-4-phenylpiperidin-4-yl)methyl)piperazine (0.135 g, 0.5 mmol) dissolved in methylene chloride (5 ml) was added diphenylmethyl isocyanate (0.115 g, 0.55 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.13 g of desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[CH:33][CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[CH:33][CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: C[C@H](Nc1ncnc2c1c(-c1cc(O)cc(NS(C)(=O)=O)c1)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ncnc2[nH]cc(-c3cc(O)cc(NS(C)(=O)=O)c3)c12)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 27.8 %

Procedure:
(S)—N-(3-hydroxy-5-(4-((1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (160 mg, 0.22 mmol) was treated with trifluoroacetic acid (4.1 mL, 53.22 mmol) and a solution of ammonia (7N in methanol, 4.1 mL, 28.7 mmol) according to the method described in Example 27 to give 34 mg (28% yield) of the title compound. Purity 99%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].OC1C(=O)N(CC(C)C)N=C(C2C=CC(C)=CC=2)C=1C>>[CH2:15]([N:13]1[C:12](=[O:19])[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:2][CH:3]=2)=[N:14]1)[CH:16]([CH3:18])[CH3:17]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(O)c2C)cc1
Product: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 1 (9), 4-hydroxy-methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 87.4%).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=1[NH2:10]>Cl.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:9]=1[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: C/C=C/C=O
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: O
Product: Cc1ccc2c(O)ccc(Cl)c2n1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Crotonaldehyde (17.5 mL, 0.21 mol) was added dropwise to a refluxing solution of 2-chloro-5-methoxyaniline hydrochloride (10.36 g. 53.4 mmol) in 5 N hydrochloric acid (450 mL) and reflux continued for a further 0.5 h. The reaction mixture was cooled and diluted with water (500 mL), then extracted with ether (400 mL). The aqueous layer was separated and basified using 50% aqueous NaOH (pH 14), and then extracted into dichloromethane (3×300 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜200 g) eluting with 20% EtOAc in hexane to give a brown oil (5.17 g) which was heated at reflux in a mixture of acetic acid (30 mL) and 48% hydrobromic acid (30 mL) for 66 h. Reaction mixture was evaporated in vacuo and the residue suspended in sat. NaHCO3 (aq), then extracted into dichloromethane (3×50 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a brown solid (2.90 g, 28%).
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:2]2[CH:21]=[CH:20][C:5]3[N:6]=[C:7]([C:12]4[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=4)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1
Yield: 58.6 %

Procedure:
Prepared from 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 1) (290 mg, 0.75 mmol) and 4-methoxy-phenylacetylene (350 mg, 1.57 mmol) according to the general procedure F. Obtained as a light yellow solid (172 mg).
Reaction SMILES: BrC1C(C)(C)CC2C(C=1)=CC=C(OC)C=2.BrC1C=CC(OC)=CC=1[N+]([O-])=O.[CH3:28][O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[N+:50]([O-])=O)[C:36]([CH3:41])([CH3:40])[CH2:37]2)=[CH:32][CH:31]=1>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:35]2[C:36]([CH3:40])([CH3:41])[CH2:37][C:38]3[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:39]=3)[CH2:34]2)=[C:43]([NH2:50])[CH:44]=1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccc(OC)cc1[N+](=O)[O-])=C2
Agent: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: COc1ccc2c(c1)CC(C)(C)C(Br)=C2
Product: COc1ccc(C2Cc3ccc(OC)cc3CC2(C)C)c(N)c1
Yield: 86 %

Procedure:
Synthesized from 3-bromo-7-methoxy-2,2-dimethyl-1,2-dihydronaphthalene and 4-bromo-3-nitroanisole according to an analogous synthetic method to Preparation Example 107 described below, 7-methoxy-3-(4-methoxy-2-nitrophenyl)-2,2-dimethyl-1,2-dihydronaphthalene (1.9 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (1.5 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
10-Bromodecan-1-ol (4.6 g) was dissolved in 20 ml of dried THF, and sodium hydride (933.6 mg) was added to this solution. The reaction mixture was stirred at room temperature for 30 minutes, then benzyl bromide (2.78 ml) was added using a syringe, and the reaction mixture was refluxed for 24 hours while stirring. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:dichloromethane=8:2) gave 1-((10-bromodecanoxy)methyl)benzene as a colorless oil at an 88% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH2:20][N:21]([CH3:37])[C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][N:26]3C1CCCCO1)=[CH:7]2.C([O-])(O)=O.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH2:20][N:21]([CH3:37])[C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: Cc1ccccc1-n1c(CN(C)c2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1-n1c(CN(C)c2ncnc3[nH]cnc23)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
8-Methyl-3-((methyl(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)methyl)-2-o-tolylisoquinolin-1(2H)-one (4003) (180 mg 0.36 mmol) was dissolved in MeOH (HCl) (50 mL) and the mixture was stirred at RT for 2 h. Aqueous NaHCO3 solution was added to the reaction mixture and the pH value was adjusted to 9. The mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product, 8-methyl-3-((methyl(9H-purin-6-yl)amino)methyl)-2-o-tolylisoquinolin-1(2H)-one (4004) (80 mg, 54% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=[N:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28](=[O:29])[C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[N:26][CH:25]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-3-pyridinecarboxylic acid (CAN 3222-49-9) as starting materials; MS (EI) 422.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]12[CH2:29][CH2:28][C:25]3([CH2:27][O:26]3)[CH2:24][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[CH3:30][O-:31].[Na+]>>[CH2:1]([C:3]12[CH2:29][CH2:28][C:25]([CH2:27][O:31][CH3:30])([OH:26])[CH2:24][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: C[O-]
Reactant: CCC12CCC3(CO3)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Agent: [Na+]
Product: CCC12CCC(O)(COC)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 50 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with rac-(2′R,4aS,12bR)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-oxirane] (93, R1=2-Methylpyridin-4-yl, R2=Ethyl) (0.200 g, 0.513 mmol) and NaOMe (0.5 M in MeOH) (5.1 mL, 2.57 mmol). The resulting solution was allowed to stir at rt for about 16 h, after which the reaction solution was concentrated under reduced pressure. The residue was partitioned between a mixture of water (20 mL) with sat. aq. NH4Cl (5 mL) and EtOAc (25 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The sample was purified on silica gel (4 g, EtOAc). Collection and concentration of the appropriate fractions gave rac-(3R,4aS,12bR)-12b-ethyl-3-(methoxymethyl)-9-(2-methylpyridin-4-yl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (94, R1=2-methylpyridin-4-yl, R2=Ethyl, R3=Methoxymethyl) (198 mg, 92%). LC/MS, method 2, Rt=2.04 min, MS m/z 422 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.8 Hz, 1H), 8.20 (s, 1H), 7.86-7.72 (m, 2H), 7.64 (s, 1H), 7.53 (s, 1H), 4.39-4.30 (m, 1H), 3.81-3.71 (m, 1H), 3.33 (s, 3H), 3.19-3.02 (m, 2H), 2.87-2.70 (m, 3H), 2.53-2.45 (m, 1H), 2.38-2.20 (m, 3H), 1.96-1.85 (m, 1H), 1.82-1.65 (m, 2H), 1.63-1.36 (m, 4H), 1.34-1.22 (m, 1H), 0.60 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1)[C:12]#[N:13].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(S(C)(=O)=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (1.0 mL) was added methanesulfonyl chloride (10.9 μL, 0.141 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (3.5 mg, 6.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.3 Hz, 6H), 1.88-1.96 (m, 2H), 2.09-2.16 (m, 2H), 2.76 (t, J=5.9 Hz, 2H), 2.89-2.96 (m, 2H), 2.97 (s, 3H), 3.24-3.30 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.10-4.16 (m, 3H), 4.81-4.85 (m, 1H), 5.66 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.68 (ddd, J=8.6, 2.0, 1.3 Hz, 1H), 7.86 (dd, J=11.4, 2.0 Hz, 1H); ESI-MS m/z [M+H]+ 489.5.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.Cl>C(=O)(O)[O-].[Na+]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:27])[F:28])[CH:21]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (7 g), m-trifluoromethylphenol (20 g), and 1N sodium bicarbonate (100 ml) was stirred at 95° C for 6 hours. Then the reaction mixture was acidified by the addition of 4N hydrochloric acid and the excess of trifluoromethylphenol was removed by steam distillation. After cooling, the precipitated 3-nitro-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid was collected by suction and recrystallized several times from methanol-water. The melting point of the pure compound was 205°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:16]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:17]=[N-:18]
Reactant: COc1cccc(C2(O)CCCCC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2(N=[N+]=[N-])CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of 1-[3-(methyloxy)phenyl]cyclohexanol (2.93 g, 14.22 mmol, 1 equiv) in CH2Cl2 (25 ml) under nitrogen at 0° C. was added sodium azide (1.85 g, 28.44 mmol, 2 equiv) then TFA (4.4 ml, 56.89 mmol, 4 equiv) slowly. 40 Ml of CH2Cl2 were then added and the resulting suspension was stirred at room temperature for 16 h then partitioned between Et2O and H2O. The two layers were separated and the organic phase was washed with H2O and a 1N aqueous NaOH solution then dried over MgSO4 and concentrated in vacuo to give 1-(1-azidocyclohexyl)-3-(methyloxy)benzene (D315) (2.78 g, 85%) as a clear oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](O)=[O:13])[CH2:4][CH2:3]1.P(Cl)(Cl)[Cl:17].Cl>>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([Cl:17])=[O:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C(=O)O)c2ccccc21
Reactant: ClP(Cl)Cl
Agent: Cl
Product: CC1(C)CCC(C(=O)Cl)c2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 195.8 %

Procedure:
102 g of 1,1-dimethyl-tetralin-4-carboxylic acid are treated while stirring with 27.4 g of phosphorus trichloride and the mixture is stirred at 50° C. for 3 hours. This treatment is carried out while excluding moisture and conducting away the resulting hydrochloric acid gas. The upper phase is separated after 12 hours and distilled over a short Vigreux column. There are obtained 87 g of 1,1-dimethyl-tetralin-4-carboxylic acid chloride of boiling point 89° C./0.2 mmHg; nD20 =1.5418-20; yield 78%.