Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[S:24][C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=2)=[O:19])[CH2:9][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:11])=[CH:3][CH:2]=1.C([N:37](C(C)C)CC)(C)C.ClC(OCC(C)C)=O.[OH-].[NH4+].Cl>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])[C@H:10]([CH3:11])[CH2:9][C@H:8]([NH:17][C:18]([C:20]1[S:24][C:23]([C:25](=[O:27])[NH2:37])=[CH:22][CH:21]=1)=[O:19])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)[CH3:16]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(C(=O)O)s1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(C(N)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-thiophene-2-carboxylic acid (115 mg, 0.247 mmol) in THF (1 mL) at 0° C. is added diisopropylethylamine (63.8 mg, 0.494 mmol) followed by dropwise addition of a solution of isobutyl chloroformate (33.7 mg, 0.247 mmol) in THF (0.1 mL). The mixture is stirred at 0° C. for 30 minutes then ammonium hydroxide (0.3 mL of 14.8 M solution) is added. The mixture is allowed to warm to room temperature then aqueous 1M HCl (3 mL) is added. Most of the THF is removed under reduced pressure and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester. MS 465.3 (M+1).
Reaction SMILES: CO[CH2:3][C:4]1[NH:18][C:17]2[C:19]3[C:5]=1[CH2:6][C@@H:7]1[C@@H:12]([C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]([CH2:20][C:21]#[N:22])[CH2:9][N:8]1[CH2:23][CH2:24][CH3:25]>C(Cl)(Cl)Cl>[CH3:3][C:4]1[NH:18][C:17]2[C:19]3[C:5]=1[CH2:6][C@@H:7]1[C@@H:12]([C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]([CH2:20][C:21]#[N:22])[CH2:9][N:8]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCN1C[C@H](CC#N)C[C@@H]2c3cccc4[nH]c(COC)c(c34)C[C@H]21
Solvent: ClC(Cl)Cl
Product: CCCN1C[C@H](CC#N)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21

Procedure:
(2-methoxymethyl-6-n-propyl-8beta-ergolinyl)-acetonitrile, yield 91%, [α]D =-91° (0.5% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of N-(3-aminophenyl)-3-nitrobenzenesulfonamide (1.00 g, 3.41 mmol) and 2,4,5-trichloropyrimidine (0.57 g, 3.1 mmol) in DMF (10 mL) was added potassium carbonate (0.52 g, 3.7 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude was purified by combi-flash column chromatography to give the desired product (1.2 g, 88%). LCMS for C16H11Cl2N5O4S (M+H)+: m/z=439.9, 441.9. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.51 (s, 1H), 8.54 (t, J=2.1 Hz, 1H), 8.43 (ddd, J=8.2, 2.0, 1.0 Hz, 1H), 8.37 (s, 1H), 8.18 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.50 (t, J=2.0 Hz, 1H), 7.29 (ddd, J=8.2, 2.0, 1.2 Hz, 1H), 7.24 (m, 1H), 6.88 (ddd, J=8.0, 2.0, 1.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 5-allyl-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.59 g, 1.63 mmol) (from Example 18, Step D, supra) in acetone (175 mL) was added K2CO3 (0.68 g, 4.91 mmol) and methyl iodide (2.32 g, 16.4 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 3 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine as an off white solid. (Yield 0.29 g, 48%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl.O>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=[CH:18][C:13]=2[CH:12]=[O:11])=[CH:26][CH:25]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCOc1ccc(-c2cc(CO)ccc2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCOc1ccc(-c2cc(C=O)ccc2C=O)cc1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (8.4 g, 5.7 ml, 66 mmol) were added to 70 ml of dichloromethane and the mixture was cooled to −60° C. A solution of DMSO (10.2 g, 9.3 ml, 131 mmol) in 30 ml dichloromethane was added dropwise over a period of 10 minutes. The mixture was stirred further for 5 minutes. A solution of 2,5-bis(hydroxymethyl)-4′-hexyloxybiphenyl (10 g, 32 mmol) (cf. D1) in 70 ml of dichloromethane was then added dropwise over a period of 15 minutes (the reaction solution became turbid). It was stirred further for 10 minutes and triethylamine (15.9 g, 21.8 ml, 157 mmol) was subsequently added dropwise. During this addition, the reaction solution became yellow and a precipitate formed. The acetone/dry ice bath was removed and the mixture was stirred for 2 hours at RT. This resulted in a light-colored solid floating on the yellow liquid phase. The mixture was admixed with 150 ml of water, stirred further for 10 minutes (the solid went into solution), the organic phase was separated off, the aqueous phase was extracted twice with dichloromethane, the combined organic phases were subsequently washed three times with water, dried over Na2SO4, filtered and subsequently evaporated to dryness on a rotary evaporator. The yellow oil crystallized after some time at RT; it was subsequently recrystallized from hexane. It took a relatively long time for the product to become solid: pale beige, microcrystalline powder, 5.67 g (57%), purity about 98%. Melting point: 44.5-45.5° C.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:32]1[C:33]2[CH:40]=[CH:39][NH:38][C:34]=2[N:35]=[CH:36][N:37]=1>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:32]2[C:33]3[CH:40]=[CH:39][NH:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
N-Ethyldiisopropylamine (1.676 ml, 9.62 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (1 g, 3.21 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.493 g, 3.21 mmol) in butan-1-ol (15 ml). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (842 mg) as a white foam. (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide was stirred in ethyl acetate (7 mL) for 18 hours. The solid was collected by filtration, washed with a small amount of ethyl acetate and vacuum oven dried at 55° C. for 18 hours to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.585 g, 42.5%) as a white solid. m/z (ES+) (M+H)+=429; HPLC tR=1.60 min.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.N1CCCCC1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1>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.[Cu]I>[OH:35][C@:31]([C:28]1[CH:27]=[C:26]([CH3:25])[O:30][N:29]=1)([CH3:32])[C:33]#[C:34][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2CCO3)no1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
To a pressure tube was added 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide (99 mg, 0.28 mmol) followed by piperidine (2.0 mL), tetrakis(triphenylphosphine)palladium (0) (32 mg, 0.03 mmol), copper(I) iodide (5 mg, 0.03 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (63 mg, 0.42 mmol). The reaction vessel was sealed and heated at 60° C. for 30 minutes. The reaction mixture was cooled and concentrated in vacuo. and then co-evaporated with dichloromethane (2×10 ml). The crude material was purified by FCC (silica, 2-8% methanol in dichloromethane) to provide 59 mg (56%) of the title compound as a pale brown solid. 1H NMR (DMSO, 500 MHz) δ 1.80 (3H, s), 2.41 (3H, s), 3.17 (2H, t, J=5.8 Hz), 4.49 (2H, t, J=5.8 Hz), 6.32-6.39 (1H, m), 6.52 (1H, s), 6.72 (1H, s), 7.21 (1H, d, J=8.4 Hz), 7.34 (1H, s), 7.37 (1H, dd, J=8.4, 2.1 Hz), 7.79 (1H, s), 8.02 (1H, d, J=2.1 Hz); M+23=401.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(N(C(C)C)CC)(C)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1.N>CO.C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:37]([NH:36][C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:39])[F:40])[CH:31]=4)=[O:38])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 50.3 %

Procedure:
Charge a 50 mL flask equipped with a magnetic stir bar, 4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzylamine (720 mg, 2.79 mmol), di-isopropyl ethyl amine (723 mg, 0.93 mL, 5.6 mmol), and THF (28 mL). Purge the flask with N2, and add 3-trifluoromethylphenyl-isocyanate (1.04 g, 0.77 mL, 5.6 mmol) via syringe. Mix the reaction at room temperature for 24 hours. Evaporate the reaction in vacuo, and chromatograph the residue using SiO2 eluting with a gradient of 1% to 15% of 2 M NH3 in MeOH with the balance CH2Cl2. Evaporate the fractions containing the product under reduced pressure, and vacuum oven dry the resulting ivory solid at 40° C. to give the title compound 624 mg (50.3%). MS(ES), m/z 445.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].O.C(=O)([O-])[O-].[Na+:19].[Na+].OS(O)(=O)=O>O>[C:2]([O:4][C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([O-:13])=[O:12])(=[O:3])[CH3:1].[Na+:19]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An aqueous solution of sodium acetylsalicylate was prepared using 50.0 g. of aspirin, 17.3 g. of sodium carbonate hydrate and 1,425 ml. water at room temperature (25° C.). After solution of all solids had occurred, 15.0 g. of instant tea was added while stirring at room temperature (25° C.). To the aqueous solution was added with rapid stirring in about 5-30 seconds 140 ml. of 2N H2SO4 and stirring was continued for 15 minutes at room temperature. The pH of the reaction mixture was after acidification was 2.6. The aqueous slurry under constant agitation was immediately thereafter spray dried in a Nichols portable spray drier (Minor Type 53) using a Nitro atomizer having a rotational speed of 31,000 r.p.m. The operating temperatures were 165° C. on the inlet side and exhaust temperatures were just under 80° C. The spray dried product weighed 76.2 g. and was light tan in color. Analysis of the spray dried product containing the coprecipitate showed it contained 56% aspirin, 0.32% salicylic acid and 1.8% water. Tea content of the spray dried product is approximately 18.8 weight %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.ClS([N:19]=[C:20]=O)(=O)=O.CN(C)C=O.O>C(COC)OC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:19])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A sample of 2-p-chlorophenyl-3-cyanopyrrole, prepared by the method of Example 4, (3.0 g, 0.015 mole) is dissolved in 50 mL of dry dimethoxyethane. To this solution is added chlorosulfonyl isocyanate (3.39 g, 0.024 mole). The addition is exothermic and some cooling is necessary. After stirring 3 hours at room temperature, dimethylformamide (6-7 mL) is added and the solution is stirred 4 hours more. The solution is then poured into water precipitating a white solid (3.4 g, 100%). A sample (1.0 g) is purified by dissolving in ethyl acetate and then passing the solution through a 60 mL course filter funnel packed with silica gel. The filtrate is concentrated to yield 0.7 g of a white solid with mp 235°-240° C.
Reaction SMILES: [F:1]C(F)(N(CC)CC)C(F)C(F)(F)F.[CH3:15][N:16]([CH3:32])[C:17]([C@H:19]1[CH2:23][C@@H:22](O)[CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18].[F-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[CH3:15][N:16]([CH3:32])[C:17]([C@H:19]1[CH2:23][CH:22]([F:1])[CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: CN(C)C(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CC(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.89 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 10 minutes, and under ice cooling, to a suspension of 2.64 g of the compound obtained in step 6-1 and 545 mg of sodium fluoride in 26 mL of dichloromethane, after which the reaction mixture was stirred for 16 hours at room temperature. After this, 100 mL of a 5% potassium carbonate aqueous solution was added under ice cooling to the reaction solution, and the reaction mixture was stirred for 30 minutes at the same temperature. After liquid separation, the aqueous layer thus obtained was extracted with chloroform (30 mL×2), and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain 2.17 g of the titled compound (colorless solid).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:15][SH:16].O>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][S:16][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1)[CH3:20]
Reactant: CCOC(=O)CS
Reactant: Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1cnc(N)s1
Temperature: 0 °C
Yield: 50 %

Procedure:
5-Bromo-2-aminothiazole (25 g, 96 mmol) and K2CO3 (26.5 g, 192 mmol) was suspended in DMF (50 mL) and stirred to 0° C. Ethyl thioglycolate (11.6 mL, 96 mmol) was added during 10 min. The reaction mixture was allowed to reach room temperature and stirred for further 13H. Addition of water (100 mL) and EtOAc (150 mL). Separation of the organic phase followed by extraction of the aqueous phase with EtOAc (2×100 mL). The combined organic phases were washed with aqueous NaHCO3 (2000 mL), brine (2×200 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (ISCO 330 g silica column, eluent A: heptane/B: 2% TEA in EtOAc. Gradient from 30% B->100% B.) to give 50-65% pure (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester as a dark red-brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4- [(5,6-dihydro-5,5-dimethyl-8-(4-(1,1- dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH--H2O in 6 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with 1M HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][N:4]=1)[CH3:2].Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: CCc1nnc(N)s1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nnc(Nc2cc(Br)cn(C)c2=O)s1
Temperature: 100 °C
Yield: 46.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-ethyl-1,3,4-thiadiazol-2-amine (500 mg, 3.88 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.55 g, 5.81 mmol), Pd2(dba)3 (357 mg, 0.39 mmol), XantPhos (451 mg, 0.78 mmol), Cs2CO3 (2.5 g, 7.67 mmol), and 1,4-dioxane (40 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. for 2 h. The mixture was cooled to 90° C. and filtered. The filtrate was cooled in an ice-water bath and then filtered again to afford 332a (574 mg, 47%) as a white solid. MS-ESI: [M+H]+ 315.1
Reaction SMILES: CC(C)([O-])C.[K+].[I:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=2.[CH3:19][O:20][C:21](=[O:26])[CH:22](Br)[O:23][CH3:24].[I-].[K+]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:26])[CH:22]([O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([I:7])=[CH:17]2)[O:23][CH3:24]
Reactant: COC(=O)C(Br)OC
Reactant: Oc1ccc2ncc(I)cc2c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: COC(=O)C(OC)Oc1ccc2ncc(I)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of potassium t-butoxide (1.36 g) in t-butyl alcohol (50 mL) was added a solution of 3-iodo-quinolin-6-ol (3 g) in t-butyl alcohol (5 mL). The reaction mixture was stirred at room temperature for 15 minutes. Bromo-methoxy-acetic acid methyl ester (4.0 g) and a solution of potassium iodide (catalytic quantity) in t-butyl alcohol (5 mL) were then added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured on water and chloroform was added. The mixture was stirred. The two layers were separated, the aqueous layer was extracted with chloroform (twice). The organic layers were combined, washed with brine (twice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude (4.3 g) was used directly in the next step without purification.