Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[CH2:19](O)[CH3:20].Cl>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1

Procedure:
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (40 g, 143 mmol) was dissolved in 20% EtOH—HCl solution (200 ml) and refluxed for 3 h to convert the starting material to ester. The volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate (×2). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by re crystallization to ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (38 g) as pale yellow solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=3)[NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[ClH:1].[F:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2[nH]c(=O)c3cc(F)ccc3c2OCCCN2CCCCC2)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=c1[nH]c(-c2cccc(O)c2)c(OCCCN2CCCCC2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 68 mg (0.166 mmol) of 7-fluoro-3-(3-methoxy-phenyl)-4-(3-piperidin-1-yl-propoxy)-2H-isoquinolin-1-one hydrochloride (cmpd. 43) in anhydrous dichloromethane (1 mL), boron tribromide (1M in dichloromethane) (1 mL, 1 mmol) was added and the mixture was stirred overnight at room temperature under argon atmosphere. The solvent was concentrated under reduced pressure and the crude was purified by flash chromatography (eluant: starting with dichloromethane/methanol/acetone/7N ammonia in methanol: 93/3/3/1 to 88/6/5/1) to afford the free base, which was then converted into the hydrochloride salt according to common chemical procedures (58 mg of the title compound, 81%).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:20](=[O:22])[C:19]2[CH:18]=[CH:17][C:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:24][CH:23]=2)[CH2:52][CH2:53]1)=[O:69]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 62.1 %

Procedure:
DIPEA (220 mg, 0.3 mL, 0.94 mmol) was added to a stirred solution of 4-morpholin-4-yl-benzoic acid (70 mg, 0.33 mmol) in DMF (5 mL). HOBT (50 mg, 0.37 mmol) and EDCI (142 mg, 0.74 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (137 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 20%-70% EtOAc in hexane as eluent) to afford 107 mg (60.8% yield) of N-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-morpholin-4-yl-benzamide, LCMS Purity: 71.5%. 1H NMR (DMSO-d6): δ 8.4 (s, 1H), 8.0 (s, 1H), 7.82 (d, 2H), 7.64 (m, 2H), 7.04 (d, 2H), 4.2 (d, 2H), 3.8-3.46 (m, 10H), 3.3 (m, 6H).
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[N+:10]([CH2:13][C:14]([NH2:16])=[O:15])([O-:12])=[O:11].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH2:6]([C:3]1[CH:4]=[C:13]([N+:10]([O-:12])=[O:11])[C:14](=[O:15])[NH:16][C:1]=1[CH3:2])[CH3:7]
Reactant: CCC(C=O)C(C)=O
Reactant: NC(=O)C[N+](=O)[O-]
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-ethyl-3-oxobutanal, sodium salt (7.5 g, 55 mmol), nitroacetamide (6.6 g, 63 mmol), aqueous piperidinium acetate (4.4 mL) [prepared from glacial acetic acid (42 mL), water (100 mL) and piperidine (72 mL)] in water (45 mL) was stirred at room temperature for 22 hours. The yellow precipitate was collected by filtration and air dried to yield 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]([C:22]2[N:23]([CH3:31])[N:24]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[N:6][C:7]=1[CH3:8].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=[O:39].[OH2:47]>O1CCOCC1>[F:16][C:15]([F:18])([F:17])[C:10]([OH:39])=[O:47].[C:27]([C:25]1[CH:26]=[C:22]([C:20]2[NH:1][C:2]3[C:3](=[N:4][C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:17])[F:16])=[N:6][C:7]=3[CH3:8])[N:19]=2)[N:23]([CH3:31])[N:24]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1N
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc2nc(-c3cc(C(C)(C)C)nn3C)[nH]c12
Product: O=C(O)C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide (45.8 mg, 0.106 mmol, prepared as described in the previous step) in 1,4-dioxane (10 mL) was treated with CSA (49.2 mg, 0.213 mmol) and heated to 100° C. under a reflux condenser for 3 h. The cooled mixture was then diluted with water (20 mL) and extracted twice with EtOAc (25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by RP-HPLC on a C18 column eluting with a linear gradient of 10-80% CH3CN in 0.1% TFA/H2O over 25 min to 8-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-6-methyl-2-(2-trifluoromethyl-phenyl)-7H-purine trifluoroacetic acid salt as an off-white solid. 1H-NMR (400 MHz, CD3OD) δ: 7.77 (d, J=7.6 Hz, 1H), 7.57-7.70 (m, 3H), 6.87 (s, 1H), 4.27 (s, 3H), 2.80 (s, 3H), 1.28 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H21F3N6: 415.2 (M+H). Measured: 415.2.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([F:38])([F:37])[C:28]([F:36])([F:35])[C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[N:20]=1)[NH2:18]>C(O)(=O)C>[F:38][C:27]([F:37])([C:28]([F:35])([F:36])[C:29]([F:33])([F:34])[CH:30]([F:32])[F:31])[CH2:26][O:25][C:21]1[N:20]=[C:19]([N:17]=[N:18][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: NNc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Solvent: CC(=O)O
Product: Oc1c(N=Nc2cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n2)c2ccccc2c2ccccc12
Temperature: 110 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (54 ml) and 9,10-phenanthrenequinone (3.8 g), and the temperature was raised to 110° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 2-hydrazino-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)pyridine (10 g) was added in 30 minutes. After stirring at 110° C. for one hour, the reaction mixture was filtrated. Crystals were stirred in methanol (100 ml) for 30 minutes, filtrated and dried to give intended crystals (5.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[C:6]([N+:14]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[C:6]([NH2:14])[CH:5]=1
Reactant: COC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NCCO)c(N)c1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 4-(2-hydroxy-ethylamino)-3-nitro-benzoic acid methyl ester (3.0 g, 12.4 mmol) in methanol was added 10% Pd/C (800 mg). The mixture was hydrogenated at 1 atmospheric pressure for 2 h. The catalyst was filtered off and the methanol evaporated to give 2.6 g (99%) of 3-amino-4-(2-hydroxyethylamino)-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([NH:17][NH2:18])=[O:16])[N:9]=2)[CH:5]=[C:4]([O:19][CH:20]([CH3:22])[CH3:21])[N:3]=1.[CH3:23]OC(OC)OC.CS(O)(=O)=O.CO.ClCCl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:16][CH:23]=[N:18][N:17]=3)[N:9]=2)[CH:5]=[C:4]([O:19][CH:20]([CH3:22])[CH3:21])[N:3]=1
Reactant: CC(C)Oc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(Cl)n1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(Cl)n1
Temperature: 70 °C
Yield: 2.3 %

Procedure:
In a 100 mL, 3-neck round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(2-chloro-6-isopropoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (1.11 gm, 1.0 eq.) was dissolved in THF (17 mL, 15V). Trimethylorthoformate (0.364 g, 1.1 eq.) was added followed by methane sulphonic acid (0.178 g, 0.5 eq.). The Reaction mixture was refluxed at 70° C. for 2 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase. Reaction mixture was poured in to ice water (500 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine solution (3×15 mL), dried over NaSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 1 g of Crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25 mL fraction each) from 35-40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (26 mg), Yield: 0.026 g (2.6%), 1H NMR: (400 MHz, DMSO) δ =10.25 (s, 1H), 8.50 (s, 1H), 7.608-7.610 (d, 1H), 7.524-7.496 (s, J=11.2, 1H), 6.359-6.360 (d, 1H), 6.316-7.288 (s, J=11.2, 1H), 5.385-5.323 (m, 1H), 1.42-1.38 (s, 6H). LC-MS: Calculated for C15H14ClN5O2(M+H)+332.75 Found: 332.8 at 3.354 min (93.31%).
Reaction SMILES: [CH:1]1([N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C(NC(C)C)(C)C>CN(C)C=O>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:15]3[CH2:16][CH2:17][CH:12]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:13][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: c1cncc(CN(C2CCNCC2)C2CC2)c1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2cccnc2)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-piperidin-4-yl-pyridin-3-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (26%, light brown solid). HPLC-MS m/z=(M+1) 513.3, Rt: 2.64 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (0.632 mole) of ethyl bromoacetate, 87.5 g (632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotorary evaporator at 45° C. and at 85° C. (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1M potassium carbonate, once with 100 ml of water, 100 ml of 0.01M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75° C. (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][NH:13][C:14](=O)[CH:15]=2)[CH:5]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][CH:14]1[NH:13][N:12]=[CH:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH:2][CH3:1])=[O:17])=[CH:15]1
Reactant: CNC(=O)c1cccc(-c2cn[nH]c(=O)c2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CNC(=O)c1cccc(C2=CC(Cl)NN=C2)c1
Temperature: 110 °C

Procedure:
N-Methyl-3-(6-oxo-1,6-dihydro-pyridazin-4-yl)-benzamide (1 eq, 3.14 mmol, 720 mg) is suspended in POCl3 (10 ml) and the reaction mixture is heated at 110° C. for 2 h. After cooling to room temperature, the solvent is removed in vacuo and then ice water is added. The pH is adjusted to pH8 with portionwise addition of sat. aqueous Na2CO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried over MgSO4, filtered and evaporated to dryness to yield 3-(6-Chloro-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide as a yellow solid which did not require further purification; [M+H]+=248
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CN1CCN(C(=O)c2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)CC1

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and N-methylpiperazine gave 202. MS: (ESI+) 496.2
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH:30]=O>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc2ccccc2[nH]1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1H-indole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 365.03 g/mol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:21])[CH:8]=2)[N:3]=1.C(OC([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[C:31](=[O:39])[NH:30]1)=O)(C)(C)C.C1COCC1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH:18]1([C:16]2[CH:17]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([I:21])[CH:8]=4)[N:3]=[C:2]([NH:38][C:35]4[CH:36]=[C:37]5[C:32]([C:31](=[O:39])[NH:30][NH:29]5)=[CH:33][CH:34]=4)[N:11]=3)[NH:14][N:15]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(I)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(I)ccc4n3)ccc12
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To (2-Chloro-6-iodo-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (208 mg, 0.606 mmol) in NMP (1 mL) was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (252 mg, 1.01 mmol) and THF (3 mL) and the solution was heated to 100 C in a sealed tube. After 4 h, the solution was poured into sat. NaHCO3, and extracted with ethyl acetate, dried (Na2SO4) and concentrated in vacuum to give the title compound as a white solid (300 mg, 95% yield). LCMS m/e: 625.2 (M+H), 623.2 (M-H).
Reaction SMILES: [CH2:1]([N:8]([C@H:13]1[C@H:17]([OH:18])[CH2:16][O:15][CH2:14]1)[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>CC(O)(C)C>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][O:18][C@@H:17]2[CH2:16][O:15][CH2:14][C@@H:13]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(Cc1ccccc1)[C@@H]1COC[C@H]1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1CO[C@@H]2COC[C@H]2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-N-benzyl-2-chloro-N-(4-hydroxytetrahydrofuran-3-yl)acetamide (4.7 g, 17.4 mmol) in t-BuOH (40 mL) was added KOt-Bu (1.0 M in THF; 34.8 mL, 34.8 mmol) solution at 25° C. The reaction mixture was stirred at 25° C. for 2 hours and then the solvent was evaporated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (100 mL). The organic extract was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford trans-4-benzyltetrahydro-2H-furo[3,4-b][1,4]oxazin-3(4H)-one. MS APCI calc'd for C13H15NO3 [M+H]+ 234. found 234.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][CH:27]2[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.S(Cl)(Cl)=O.[CH3:38]O>>[C:31](=[O:33])=[O:32].[F:1][C:2]1[CH:3]=[C:4]([NH:26][C@@H:27]2[CH2:30][C@H:29]([C:31]([O:33][CH3:38])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: O=C(O)C1CC(Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Product: O=C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-phenylamino)-cyclobutanecarboxylic acid (230 mg, 0.501 mmol) was added methanol (5.0 mL) and thionyl chloride (37 μl, 0.501 mmol) before it was stirred at ambient temperature for 30 min; the reaction mixture was concentrated, and the diastereomers were separated via SFC (Column: ChiralPak AS-H, Mobile Phase: liquid CO2/20% MeOH with diethylamine; then Column: Princeton Pyridine, Mobile Phase: liquid CO2/12% MeOH) to give methyl cis-3-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)-cyclobutanecarboxylate. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++H).
Reaction SMILES: ClC1C=C2[C:8](=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6]([C:20]([O:22]CC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].[NH:57]1CCOCC1.OC1CNC1>>[OH:22][CH:20]1[CH2:6][N:7]([S:53]([C:33]2[C:32]3[C:36](=[CH:37][CH:38]=[C:30]([I:29])[CH:31]=3)[NH:35][C:34]=2[C:48]([NH2:57])=[O:50])(=[O:54])=[O:55])[CH2:8]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Agent: OC1CNC1
Product: NC(=O)c1[nH]c2ccc(I)cc2c1S(=O)(=O)N1CC(O)C1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 3-hydroxyazetidine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 421.88 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.[Cl-].[CH3:28][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:10]4[C:2]([CH3:28])=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccn1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2nc(C)n3c2c1OCC3c1ccccn1
Temperature: 150 °C
Yield: 49 %

Procedure:
A mixture of 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (45 mg, 0.12 mmol), 2.0 M methylzinc chloride in THF (310 μL), and tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) in THF (2 mL) under nitrogen was heated in a microwave at 150° C. for 5 min. Purification by preparative LCMS using pH 10 buffer gave the title compound (21 mg, 49%). LCMS calc. for C20H19N4O2 (M+H)+: m/z=347.1. found: 347.2. 1H NMR (300 MHz, CD3OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.69 (td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1, 5.3 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09 (m, 1H), 4.00-3.71 (m, 2H), 3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23-2.11 (m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:24][CH2:23][CH2:22][C:10]3([CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:9]2)[CH:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:24][CH2:23][CH2:22][C:10]3([CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9]2)[CH:3]=1
Reactant: Cc1ccnc(N2CCCC3(CCN(C(=O)OC(C)(C)C)C3)C2)c1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(N2CCCC3(CCNC3)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The residue of step A was dissolved in a mixture of methanol and hydrochloric acid (4M in dioxane, 5 ml) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to yield 79 mg of a solid (quantitive) that was used directly in the next step.