Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[CH2:6][CH:5]2[NH:15][CH:4]12)[CH3:2].[BrH:18].C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(O)C>[BrH:18].[NH2:15][CH:4]1[C:3]([CH2:16][CH3:17])([CH2:1][CH3:2])[C:12]2[CH:11]=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]1[Br:18]
Reactant: CCC1(CC)c2cc(OC)ccc2CC2NC21
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC1(CC)c2cc(O)ccc2CC(Br)C1N
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To a flask was added 7,7-diethyl-5-methoxy-1a,2,7,7a-tetrahydro-1H-1-aza-cyclopropa[b]naphthalene (268 g, 1.16 mol) and hydrogen bromide (1.97 L, 17.38 mol), followed by tetra-N-butylammonium bromide (38 g, 0.12 mol). The reaction mixture was heated at 100° C. overnight with stirring, cooled to room temperature and then poured into stirred ethyl acetate (2.5 L). The product was isolated by filtration, the filter cake was washed with ethyl acetate (2×200 mL) and dried to yield crude product (370 g) as a purplish solid. The crude product was suspended in ethanol (1.50 L) then heated at 80° C. for 30 min. The resulting slurry was cooled to room temperature over 1 h, and filtered. The flask and filter cake with were washed with ethanol (2×100 mL) and then with ethyl acetate (100 mL) and dried overnight to yield the title compound (275 g, ˜96% purity).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([N+:28]([O-:30])=[O:29])=[C:23](F)[C:22]=1[F:32]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:23]2[C:24]([N+:28]([O-:30])=[O:29])=[C:25]([F:27])[CH:26]=[C:21]([F:20])[C:22]=2[F:32])=[C:4]([F:9])[CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (2.0 g, 10.5 mmol) in THF (80 mL) was dropwise added LHMDS solution (12.6 mL, 12.6 mmol, 1 M in THF) at −78° C. After stirring at −78° C. for 1 h, a solution of 1,2,3,5-tetrafluoro-4-nitro-benzene (2.05 g, 10.5 mmol) in THF (20 mL) was added dropwise into the reaction mixture, which was stirred at −78° C. for 1 h, and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was re-crystallized in hexane to yield (4-bromo-2-fluoro-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine as a yellow solid (1.6 g). 1H-NMR (400 MHz, CDCl3): δ 6.73-6.75 (1H, m), 6.86-6.87 (1H, m), 7.22 (1H, d, J=8.4), 7.30 (1H, dd, J=2.0 Hz, 10.8), 7.71 (1H, s).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([C@H:32]([OH:37])[C@H:33]([OH:36])[CH2:34]O)[CH:30]=[O:31].[BH4-].[Na+]>CO.C(O)(=O)C>[CH:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][CH2:34][C@H:33]([OH:36])[C@@H:32]([OH:37])[C@H:29]([OH:28])[CH2:30][OH:31])[N:15]=2)=[CH:23][C:20]=1[C:21]#[N:22])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NC[C@H](O)[C@@H](O)[C@H](O)CO)no2)cc1C#N
Temperature: 50 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
Prepared using General Procedure 13. To a solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (50.mg, 0.14 mmol) in MeOH (10 mL) was added (2S,3R,4R)-2,3,4,5-tetrahydroxypentanal (20.71 mg, 0.14 mmol) and acetic acid (2 drops) with stirring at 50° C. for 18 h. The reaction was cooled to room temperature and sodium borohydride (52.2 mg, 1.38 mmol) was added slowly with stirring for 2 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3 aqueous (10 mL) and extracted with EA (3×10 mL). The organic layers were washed with brine and dried over Mg2SO4. The product was purified by preparative HPLC to give 8.68 mg (25%) of 2-isopropoxy-5-(3-((S)-1-(((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 119 as a solid. LCMS-ESI (m/z) calculated for C26H30N4O6: 494.5. found 495.2 [M+H]+, tR=2.42 min.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C@H:19]([NH:18][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:12]=1)=[O:15])[C:20](=[O:21])[NH:22][CH3:23]
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1cccc(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-fluorobenzyl)picolinic acid (Example 277 a) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=372.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH2:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17][CH2:16]1)=[O:19])[CH3:22]
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3s2)CC1
Temperature: 180 °C
Yield: 73.7 %

Procedure:
A mixture of 2-chloro-benzothiazole (2.00 g, 12.0 mmol, 1.0 equiv), ethyl 4-amino-1-piperidine carboxylate (2.44 g, 14.0 mmol, 1.2 equiv) and triethylamine (1.79 g, 18.0 mmol, 1.5 equiv) was heated by microwave irradiation to 180° C. for 5 min. To the crude reaction mixture was added dichloromethane (10 mL) and the suspension quickly poured onto tert-butyl methylether (200 mL). The hydrochloric salts of remaining ethyl 4-amino-1-piperidine carboxylate and triethylamine precipitated out and were removed by filtration. The filtrate was evaporated to dryness and the residue purified with column chromatography on silica eluting with dichloromethane/methanol (95:5) to yield 2.7 g (75%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.31-1.44 (m, 2H), 1.96-2.01 (m, 2H), 2.98-3.06 (m, 2H), 3.88-3.98 (m, 3H), 4.04 (q, J=7.1 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H). MS (ISP): 306.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2c(O)cc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Then, 100 ml of an ethyl acetate solution of 10.0 g of 2'-hydroxy-4,4',6'-trimethoxychalcone was added to a suspension of 2.0 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed in advance, and the mixture was stirred at room temperature for 1 hour in a hydrogen gas atmosphere. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 9.3 g (yield=93.0%) of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1propanone in the form of a colorless needle.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29]([CH:31]4[CH2:32][CH2:33]4)=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: CC(C)c1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-isopropylphenyl)-1-butanone and N-[3-(4-piperidinyl) phenyl]cyclopropanecarboxamide: ESMS m/e: 433.2 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Cl:1][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2ccccc2n1-c1cccc(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
A solution of N-chlorosuccinimide (0.015 g, 0.11 mmol) in DMF (0.1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (35 mg, 0.099 mmol) in N,N-dimethylformamide (0.5 mL, 6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The mixture was then diluted with water and then extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc in hexane) to give the desired product (36 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=O)=[CH:5]2.[H-].[Na+].[C:18](OCCCC)(=O)[CH:19]=C.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:18][CH2:19][C:11](=[O:13])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: C=CC(=O)OCCCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCn2c1cc1cc(Br)ccc12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (30 g, 112 mmol) in toluene (500 mL) was added portionwise sodium hydride (60% dispersion in mineral oil, 9.40 g, 235 mmol). Vigorous gas evolution was observed. The resulting white suspension was heated to 110° C. Butyl acrylate (35.1 mL, 246 mmol) was added dropwise (using a syring pump) over 24 h while stirring vigorously at an internal temperature of 110° C. Additional butyl acrylate (10 mL) was added in one portion and stirring was continued at 110° C. for 4 h followed by additional sodium hydride (60% dispersion in mineral oil, 5 g) and butyl acrylate (10 mL). 4 h later, butyl acrylate (6 mL) was added. Stirring was continued at 110° C. for a total of 48 h. The reaction was cooled in an ice-bath and 2 M HCl (400 mL) was added carefully. The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The resulting orange residue was dissolved in acetic acid (900 mL) and water (100 mL). The orange solution was refluxed 16 h before the solvents were removed under vacuum. To the residue was added dichloromethane (300 mL). The resulting precipitate was collected by filtration and rinsed twice with dichloromethane to provide the title compound. LCMS m/z=250.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.20 (t, J=6.1 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 6.92 (s, 1H), 7.46 (dd, J=8.8, 1.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].O>C(O)C>[CH2:1]([NH:4][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: COC(=O)C(C)Br
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNC(C)C(=O)OC
Yield: 60.1 %

Procedure:
To a mixture of 10 g (0.18 mole) of allylamine, 10.8 g (0.2 mole) of sodium bicarbonate in 50 ml of ethanol is added 30 g (0.18 mole) of methyl 2-bromopropionate dropwise. The resulting mixture is heated under reflux for 5 hours. The reaction mixture is cooled, poured into water, and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated under reduced pressure to give 15.5 g of a light yellow oil. This material is further purified by distillation to give 10.5 g of pure product.
Reaction SMILES: C([Sn]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(CCCC)CCCC)CCC.Br[C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][C@@H:40]([CH3:50])[C@@H:41]3[C:45]([CH:47]3[CH2:49][CH2:48]3)=[O:46])[C@H:37]3[C:28]2=[C:29]2[C:34]([CH2:35][CH2:36]3)=[CH:33][C:32](=[O:51])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:47]1([C:45]([C@H:41]2[C@H:40]([CH3:50])[CH2:39][C@H:38]3[C@H:37]4[C:28]([C@@H:27]([C:24]5[CH:25]=[CH:26][C:21]([C:18]6[CH:19]=[CH:14][N:15]=[N:16][CH:17]=6)=[CH:22][CH:23]=5)[CH2:44][C@:42]23[CH3:43])=[C:29]2[C:34](=[CH:33][C:32](=[O:51])[CH2:31][CH2:30]2)[CH2:35][CH2:36]4)=[O:46])[CH2:49][CH2:48]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccnnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in hexane) was added dropwise to a cooled (0° C.) solution of diisopropylamine (0.97 mL, 6.9 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere. After stirring for 30 minutes the reaction mixture was cooled to −78° C. and a solution of pyridazine (452 μL, 6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol) were added simultaneously while the temperature was kept below −70° C. The reaction mixture was stirred for 2 hours at −78° C.; subsequently, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to dryness. The crude product was purified by LCMS to give tributylstannylpyridazine (197 mg, 0.53 mmol, 8% yield). This stannylpyridazine (183 mg, 0.49 mmol), (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (100 mg, 0.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (3 mg, 0.004 mmol) were dissolved in dioxane (3 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by LCMS followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one (78 mg, 0.16 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.85-2.84 (m, 26H), 4.48 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.33-7.37 (m, 2H), 7.60-7.64 (m, 3H), 9.21 (dd, J=5 and 1 Hz, 1H), 9.46 (dd, J=3 and 1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([S:17](Cl)(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:13]([S:17]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NCCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 ml of 2-methoxyethylamine (5.5 g, 73.7 mmol) and 10.2 ml of triethylamine (7.4 g, 73.7 mmol) were dissolved at room temperature in 72 ml of methylene chloride. Likewise at room temperature 9.6 ml of n-butanesulfonyl chloride (11.5 g, 73.7 mmol) were added dropwise to this solution over the course of one hour. After 1 h of stirring at room temperature the reaction mixture was washed twice with 100 ml of water. The organic phase was dried over magnesium sulphate, the methylene chloride was distilled off and the oily residue which remained was dried in vacuo. This gave 12.4 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([O:10][CH3:11])[C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:7][N:6]=1
Reactant: COc1cc(OC)c(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cnc(OC)cc2OC)cc1
Yield: 99.3 %

Procedure:
According to Scheme 23 Step 3: The title compound was prepared from 5-bromo-2,4-dimethoxypyridine (1 eq, 1.40 mmol, 0.30 g) and 4-methoxyphenylboronic acid (1.5 eq, 2.10 mmol, 0.32 g) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 98/2 to afford 2,4-dimethoxy-5-(4-methoxyphenyl)pyridine (1.39 mmol, 0.34 g, 99%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(F)cc1
Temperature: 0 °C
Yield: 34.7 %

Procedure:
A solution of 7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (13.527 g, 54.7 mmol) in concentrated ammonium hydroxide (150 mL, 3852 mmol) was heated at 100° C. in a high-pressure (350 mL) vessel overnight. The reaction mixture was cooled to 0° C. and filtered. The precipitate was consecutively washed with water and dried by passing air through the filter and subsequently under vacuum to give 7-(4-fluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (4.670 g, 18.97 mmol, 34.7% yield). LC-MS (M+H)+=247.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.70-11.81 (2H, br s), 7.31-7.39 (2H, m), 7.16-7.22 (2H, m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H, m), 1.84-1.95 (1H, m).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2.[H-].[Na+].[H][H]>CC(O)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([O:8][CH:5]([CH3:6])[CH3:4])[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2
Reactant: Oc1nc(Cl)cc(N2CC3CCC(C2)O3)n1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(O)n1
Temperature: 170 °C
Yield: 85.1 %

Procedure:
4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 460 mg, 1.903 mmol) was dissolved in 2-propanol (30 mL). The mixture was divided over two 20 mL microwave vials. Sodium hydride (305 mg, 7.61 mmol) was added (153 mg to each vial), resulting in a fine suspension. The vials were stirred at room temperature until no further formation of hydrogen gas was observed. The vials were flushed with nitrogen. The mixture was heated under microwave irradiation for 1 hour at 170° C. The 2 vials were combined and made acidic with 9 mL 1N HCl to pH˜3. Silica gel was added and the solvents were evaporated. Silica gel chromatography, using a gradient (0-20%) of MeOH in dichloromethane, gave the title compound (215 mg, 0.81 mmol, 43%) as a yellow foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:11]([CH:24]=CC)=[C:12]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:29]=[O+][O-]>C(Cl)Cl.CO>[CH:24]([C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:27]=2)=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21])=[O:29]
Reactant: CC=Cc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c(C=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 5-(4-(methylsulfonyl)phenoxy)-4-(prop-1-enyl)isophthalate (2.6 g, 7.8 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil, which was introduced into a silica gel column and eluted with 10-30% EtOAc in hexanes to afford the title compound (2.5 g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.08 (q, 3 H) 3.95 (dd, 6 H) 7.08-7.16 (m, 2 H) 7.98 (q, J=2.07 Hz, 2 H) 7.99-8.03 (m, 1 H) 8.33-8.39 (m, 1 H) 10.46 (s, 1 H); LC-MS (ERS)+m/z=393.00 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:8])[CH3:7].CN([CH:21]=[O:22])C>CCOC(C)=O>[CH:6]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:21]=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc2ccccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)c1[nH]c2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (0.86 ml, 9.4 mmol) was added dropwise to anhydrous DMF (4 ml) at 0° C. with stirring. After 30 min, this solution was added dropwise to a solution of 2-isopropyl-1H-indole (Compound 38, 1.24 g, 7.8 mmol) in DMF (16 ml) at 0° C. under argon. The reaction was stirred for 1 h while it warmed up to room temperature. The reaction was diluted with EtOAc, washed with aq. NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residual solid was washed with Et2O to yield 2-isopropyl-1H-indole-3-carbaldehyde (Compound 39) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.C([N:15](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1c(F)cc(Br)cc1F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
To a stirred solution of the above benzoic acid intermediate (18 g, 76 mmol) in THF (150 mL)), at −20° C., was added triethylamine (7.6 g, 76 mmol) and ethyl chloroformate (9.8 g, 91 mmol. The reaction was stirred at −20° C. for 20 min. Then it was warmed up to room temperature and an ammonia solution (0.5 M in dioxane, 150 mL, 76 mmol) was added. The reaction was stirred at room temperature overnight. It was then concentrated, diluted with dichloromethane, washed with 1 N HCl and brine, and dried over Na2SO4. The solvent was removed to give the crude product as a solid. It was washed with dichloromethane to give 4-bromo-2,6-difluorobenzamide (9.4 g, 52.4%).