Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][C:35]=1[CH3:40].NN.Cl>CO.C1COCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[CH3:40])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (196 mg, 0.34 mmol) in MeOH/THF (2 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified on silica (50% MeOH in CHCl3 (0.5% NH4OH) to give a free base of the tile compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (107 mg, 51%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.96 (s, 1H), 7.90 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 4.66 (m, 1H), 3.91 (s, 3H), 3.33-3.14 (m, 4H), and 2.10 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:24]1[C:28]2([CH2:33][CH2:32][N:31]([C:2]3[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=3)[C:7]([NH:9][C:10]3[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=3[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC4(CC3)OCCO4)ccc2C)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a solution of methyl 3-[(5-bromo-2-methyl-benzoyl)amino]-2,4-dimethyl-benzoate (0.5 g, 1.33 mmol), 1,4-dioxa-8-azaspiro(4.5)decane (228.34 mg, 1.59 mmol) and Cs2CO3 (1.3 g, 3.99 mmol) in 1,4-dioxane (10 ml) is added Pd(OAc)2 (29.84 mg, 132.89 μmol) followed by racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (82.75 mg, 132.89 μmol). The reaction mixture is purged with nitrogen for 10 minutes and then heated to 90° C. After 3 hours, very small amount of the product is formed. To the reaction mixture is added Pd(OAc)2 (29.84 mg, 132.89 μmol) followed by racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (82.75 mg, 132.89 μmol) and heated to 100° C. After 12 hours, the reaction is cooled to ambient temperature and diluted with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-100% ethyl acetate in hexane to afford the title compound as a brown solid (0.26 g, 44.62%). Mass spectrum (m/z): 439.2 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CC(C)=O>C(Cl)Cl>[CH3:15][S:16]([O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])(=[O:18])=[O:17]
Reactant: O=C1NCC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCNC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Suspend the product of Example 1 (8 g., 79.2 mmol.) in dry methylene chloride (30 ml.) and cool to 0° C. Treat the suspension sequentially with dry triethylamine (16 ml., 118.8 mmol.) and methane sulfonyl chloride (6.74 ml., 87.12 mmol.). Stir at 5°-10° C. for 1.5 hours, and subject the mixture to flash chromatography using acetone (5-10%) in dichloromethane to yield the title compound as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[C@@H:15]([C:16](OCC)=[O:17])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>O1CCCC1>[OH:17][CH2:16][C@@H:15]1[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][C@@H:10]1[NH:9][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:8]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N[C@@H](C)c1ccccc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](N[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
The product of Example 61B (60.0 g, 0.159 mol) in tetrahydrofuran (200 mL) was added dropwise to a mixture of lithium aluminum hydride (7.00 g, 0.175 mol, 95%) in tetrahydrofuran (300 mL) at 0° C. After the addition was complete, the mixture was allowed to warm to ambient temperature and was quenched by slow addition of Na2SO4.10 H2O (excess). The mixture was stirred for 16 hours, filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50% ethyl acetate/hexanes) to provide two diastereomers, a more mobile diastereomer determined to be the (3S,4S) diastereomer Rf=0.27 in 75% ethyl acetate/hexanes, 15.0 g, 44.8 mmol, 28% yield and a less mobile diastereomer determined to be the (3R,4R) diastereomer (Rf=0.20 in 75% ethyl acetate/hexanes, 22.5 g, 67.3 mmol, 42% yield). MS (DCI/NH3) m/z 335 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:29]1([CH3:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(Br)C1C=CC=CC=1>C1COCC1>[C:15]([C:10]1([CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11](=[O:14])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: Cc1ccccc1
Agent: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A solution of 1-benzyl-3-carbomethoxy-4-piperidone (1.0 g, 4.0 mmol) in THF (10 mL) was treated with 0.5M potassium bis(trimethylsilyl)amide in toluene (9.6 mL, 4.8 mmol) for 15 min, followed by the addition of benzyl bromide (1.2 g, 4.8 mmol). After 2 h, the reaction mixture was quenched with sat. NH4Cl and extracted with ether. The combined organic layers were washed with brine, dried with MgSO4 and concentrated. The product was purified by silica gel chromatography eluting with 4:1 hexane-EtOAc to give 3-carbomethoxy-1,3-dibenzyl-4-piperidone (0.61 g) as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].[NH2:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@@H:30]([CH3:32])[OH:31]>CN(C=O)C>[NH:17]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@H:4]([C:5]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](C)O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Coupling of 7.85 g Z-Val-ONp with 5.53 p H-Thr-Leu-OtBu in 160 ml DMF in the way described in C(2) provides Z-Val-Thr-Leu-OtBu in 72% yield.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([O:3][CH2:2][CH2:1][OH:4])=[N:13][CH:12]=[C:11]([CH:10]=2)[C:14]([OH:16])=[O:15])=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(OCCO)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
To a solution of ethane-1,2-diol (301 mg, 270 μA, 4.84 mmol) in dried DMF (6 mL) was added sodium hydride (232 mg, 4.84 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was added slowly to a solution of 6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (CAN 1012792-56-1; 0.590 g, 2.2 mmol) in dried DMF (6 mL) and stirred at 80° C. for 4 h. More sodium hydride (106 mg, 2.2 mmol) was added and at room temperature and stirring at 80° C. commenced for another 2 h. Water was added and DMF was evaporated. The residue was dissolved in water; acidified with 3M HCl to pH 3. The suspension was filtered; the filter cake was washed with water and dried under high vacuo. The crude material was purified by flash chromatography (ReproFlash Acidosil-S, 50 g, 50% to 100% ethylacetate in heptane) to give 0.27 g (41%) of the title compound as a white solid; MS (ESI): 292.1 (M−H)−.
Reaction SMILES: [CH2:1]1[S:5](=[O:7])(=[O:6])[O:4][CH2:3][CH2:2]1.[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>CO>[N:8]1([CH2:3][CH2:2][CH2:1][S:5]([OH:4])(=[O:7])=[O:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=S1(=O)CCCO1
Solvent: CO
Product: O=S(=O)(O)CCCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3.45 h

Procedure:
48.8 molten propane-1,3-sultone were added dropwise at 60+ to 80° C. within the course of 50 minutes to 58.4 g 1,2,3,4-tetrahydroquinoline in a 500 ml. flask. The reaction mixture was left for 3.45 hours at about 70° C. and subsequently 470 ml. methanol were added portionwise under reflux conditions and further stirred under reflux conditions until the solid, glasslike under material had dissolved completely. Thereafter, the reaction mixture was cooled to ambient temperature, while stirring, a rapid crystallization thereby taking place. After leaving to stand for about 12 hours in a refrigerator, the crystals were filtered off. Yield about 50 g.; m.p. 233°-237° C.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:25][C:26]([O:35][CH2:36][CH3:37])=[C:27]([CH2:29][C:30]([O:32]CC)=[O:31])[N:28]=2)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>CO.O>[CH2:1]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:25][C:26]([O:35][CH2:36][CH3:37])=[C:27]([CH2:29][C:30]([OH:32])=[O:31])[N:28]=2)=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(-c2nc(CC(=O)OCC)c(OCC)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCOc1ccc(-c2nc(CC(=O)O)c(OCC)o2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of 20 g of ethyl 2-(4-hexadecyloxyphenyl)-5-ethoxy-4-oxazoleacetate in 200 ml of methanol was added a solution of 7.6 g of sodium hydroxide in 20 ml of water under stirring at room temperature and stirred for about 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and the solution was acidified with hydrochloric acid to pH 1 under cooling. The precipitate was filtered off, dried and recrystallized from methanol to give 11.7 g of the title compound of white powder, m.p. 89°-91° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>C1COCC1>[CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)C=Cc1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccncc1

Procedure:
The title compound was prepared according to General Method 3 using 4-methyl-1-pyridin-4-yl-pent-1-en-3-one (Example B-16; 1.81 g), (Ph3P)3RhCl (0.5 g), and THF (100 mL) at 50 psi. The title compound was flash chromatographed using 98:2 CH2Cl2:MeOH as eluent. 1H NMR (CDCl3): δ 1.15 (d, 6H), 2.5-2.7 (m, 1H), 2.7-2.8 (m, 2H), 2.85-2.95 (m, 2H), 7.1 (d, 2H), 8.5 (d, 2H).
Reaction SMILES: [C:1]([OH:10])(=O)[C@H:2]([C@@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=C(C)C=1>O>[CH2:11]([N:18]1[C:6](=[O:7])[C@@H:4]([OH:5])[C@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: Cc1cccc(C)c1
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of D(-)-tartaric acid (4.5 g, 30 mmol), benzylamine (3.3 ml, 30,2 mmol) and m-xylene (50 ml) was heated at reflux temperature for 4 hours with simultaneous capture of water. The mixture was cooled to room temperature, filtered and washed with m-xylene twice (2×2 ml) and acetone (10 ml) to give (3S,4S)-1-benzyl-3,4-dihydroxy-2,5-dioxopyrrolidine (5.0 g, yield: 76%) as light yellow crystals.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:28])[C:22]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:29])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3].O.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[Br:28][C:21]1[C:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:29]
Reactant: O=C1c2cccc3c(N4CCCC4)c(Br)cc(c23)C(=O)N1OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [B+3]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1c2cccc3c(N4CCCC4)c(Br)cc(c23)C(=O)N1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.23 g, 0.51 mmol, from Example W1) in TFA (5 mL) at 0° C. was added a 1.0 M solution of boron tris(trifluoroacetate) in TFA (3 mL). The reaction was stirred at 0° C. for 2 hours and poured into a water/ethanol solution (1:1). The solution was neutralized with saturated Na2CO3, the resulting precipitate removed by filtration, and chromatographed using chloroform/hexane (10:1) to give 0.10 g of the title compound, mp 170-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([CH3:9])[CH3:10])=[O:23])[N:21]=2)[CH:18]=1
Reactant: CC(C)(N)c1ccc(F)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: CC(C)(NC(=O)c1cn2cc(Br)ccc2n1)c1ccc(F)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 2-(4-fluorophenyl)propan-2-amine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11](C(O)=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.C([O:22][C:23](=[O:41])[CH2:24][C:25]1C=CC2C(=O)C3C=CC=CC=3C=CC=2C=1)C.O=C1C2C=CC(CC(O)=O)=CC=2C=CC2C=CC=CC1=2>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:24]([CH3:25])[C:23]([OH:41])=[O:22])=[CH:12][C:7]=2[CH:6]=[CH:5][C:19]2[CH:18]=[CH:17][CH:16]=[CH:4][C:3]1=2
Reactant: CCOC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
The compounds of Formula I can be prepared by conducting an Arndt-Eistert reaction upon 5-oxo-5H-dibenzo[a,d]-cycloheptene-2-carboxylic acid to afford, in various steps thereof, 5-oxo-5H-dibenzo[a,d]cyclohepten -2-acetic acid ethyl ester and 5-oxo-5H-dibenzo[a,d]cyclohepten-2-acetic acid. 2-(5-Oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, and the corresponding esters of the aforementioned acids can be obtained via alkylation and/or esterification.
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.[CH2:27]=[O:28]>C1COCC1>[Br:19][C:20]1[N:21]=[C:22]([F:26])[C:23]([CH2:27][OH:28])=[CH:24][CH:25]=1
Reactant: Fc1cccc(Br)n1
Reactant: C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1ccc(Br)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To Diisopropylamine (22.001 mmol; 2240 mg; 3.13 mL) in THF (40 mL) at 0° C. was added N-Butyllithium (2.5 mol/L) in Hexane (24.001 mmol; 9.6 mL). The reaction was stirred at 0° C. for 0.5 h, and then cooled to −78° C. 2-bromo-6-fluoro-pyridine (20.001 mmol; 3520.0 mg) in THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 2.5 h. Paraformaldehyde (40.002 mmol; 3603.3 mg) was added rapidly. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and the residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to afford (6-bromo-2-fluoro-3-pyridyl)methanol (1.4888 g, 36%).
Reaction SMILES: N[CH:2]([OH:12])[CH2:3][C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1Cl.FC1C=CC=CC=1[N+]([O-])=O>>[C:4]1([CH2:3][CH2:2][OH:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(O)Cc1c(Cl)cccc1Cl
Agent: O=[N+]([O-])c1ccccc1F
Product: OCCc1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 1.03 g of α-amino-2,6-dichlorobenzeneethanol and 0.7 g of 1-fluoro-2-nitrobenzene was stirred for 3 hours at 110° C. The reaction mixture was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.4 g (24.4%) of (±)-2,6-dichloro-β-(2-nitrophenyl)amino]benzeneethanol; m.p. 127.6° C. (comp. 12).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)(O)[O-].[Na+].C(OC([N:21]1[C:29]2[C:24](=[CH:25][C:26]([P:30]([O:34][CH3:35])([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=2)[C:23](I)=[N:22]1)=O)(C)(C)C>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.CN(C)C=O>[CH3:35][O:34][P:30]([C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[NH:21][N:22]=[C:23]2[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:31])[O:32][CH3:33]
Reactant: COP(=O)(OC)c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(OC)c1ccc2[nH]nc(-c3cccs3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 2.1 %

Procedure:
44.8 mg (0.25 eq; 0.039 mmol) of tetrakis(triphenylphosphine)palladium(0), 39.6 mg (2 eq; 0.310 mmol) of 2-thiopheneboronic acid, 3 ml of dimethylformamide and 150 μl of saturated sodium bicarbonate solution are added to 70 mg (1 eq; 0.155 mol) of 5-(dimethoxyphosphoryl)-3-iodoindazole-1-carboxylic acid tert-butyl ester. The medium is stirred at 130° C. for 5 hours. The reaction medium is filtered through paper and the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 2 mg of (3-thiophen-2-yl-1H-indazol-5-yl)phosphonic acid dimethyl ester (40% purity by NMR), along with 12.9 mg of (3-thiophen-2-yl-1H-indazol-5-yl)phosphonic acid monomethyl ester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][P:12]([CH2:19][O:20]S(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C@H:39]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH3:40])=[CH:34][CH:33]=1>>[C:44]([O:43][C:42]([NH:41][CH:39]([CH3:40])[CH2:38][C:35]1[CH:34]=[CH:33][C:32]([O:20][CH2:19][P@:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:37][CH:36]=1)=[O:48])([CH3:47])([CH3:45])[CH3:46]
Reactant: CCCCOP(=O)(CCCOCc1ccccc1)COS(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: CCCCO[P@](=O)(CCCOCc1ccccc1)COc1ccc(CC(C)NC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 3-benzyloxypropyl-(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, t-butyl ester according to the method described in Procedure 24. The crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc4[nH]ccc34)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-hydroxyindole (200 mg) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (3/1) to obtain 51 mg of the title compound (yield: 32%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17])[CH3:3].C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C>[Br:25][C:13]1[S:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[C:6]([C:16]([F:19])([F:17])[F:18])[CH:7]=2)=[N:15][CH:14]=1
Reactant: CC(C)Oc1ccc(-c2nccs2)cc1C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C(F)(F)F
Temperature: 20 °C

Procedure:
To a solution of 2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazole (D66) (143 mg) and sodium acetate (82 mg) in acetic acid (5 mL) stirred at 5° C. was added a solution of Br2 (0.026 mL) in acetic acid (1 mL) dropwise. The reaction mixture was stirred at 20° C. until start material was consumed completely. The reaction mixture was basified with 2M NaOH. The resulting solution was diluted with ethyl acetate. The mixture was washed with brine. The organic phase was dried over anhydrous sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-bromo-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazole (D67) (120 mg). δH (CDCl3, 600 MHz): 1.31 (6H, d), 4.63 (1H, m), 7.05 (1H, d), 7.70 (1H, s), 7.94 (1H, dd), 8.06 (1H, d).