Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(Br)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC(Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 104.5 %

Procedure:
A mixture of 2-bromopropanoic acid (15.3 g; 100 mmol), benzyl alcohol (13.0 g; 120 mmol) and p-toluenesulphonic acid monohydrate (50 mg) in cyclohexane (200 mL) was refluxed in a Dean-Stark apparatus for 19 h. The reaction mixture was cooled to ambient temperature, washed with saturated NaHCO3 solution (1×30 mL), water (1×30 mL) and saturated NaCl solution (1×30 mL). After drying (MgSO4), filtration, and evaporation, the residue was vacuum-distilled. 25.4 g (87%) product was obtained (colourless liquid, by 111-113° C./1.1 mm Hg).
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][NH2:18])[CH3:15]>>[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][N:18]1[C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=[C:4]1[CH3:13])[CH3:15]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)CN1C(C)=CC(=C(C#N)C#N)C=C1C

Procedure:
A solution of 0.5 g (2.9 mmol) of (2,6-dimethyl-4H-pyran-4-ylidene)malononitril in 7.6 ml (6 g, 46.4 mmol) 2-ethyl-1-hexylamine was refluxed for 1 h under nitrogen. Removal of the excess of ethyl-1-hexylamine at reduced pressure left a solid which was recrystallized from 15 ml EtOAc/MeOH 2/1 yielding 0.45 g (55%) of 1-N-(2-ethylhexyl)-4-dicyanomethylene-2,6-dimethyl-1,4-dihydropyridine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 109.3 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2,4-difluorophenyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example J-4, 0.20 g, 0.45 mmol) and triethylamine (0.34 mL, 2.4 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 6 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.23 g of the title compound as a solid, mp 212-214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([Cu])#[N:13]>N1C=CC=CC=1.CCOC(C)=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccccc2c1
Temperature: 250 °C

Procedure:
A suspension of 3-bromoquinoline (1-Im-10, 1.5 g) and CuCN (3 eq) in 10 mL of pyridine in a 25 mL microwave tube was heated at 250° C. for 30 min in a microwave. This was repeated 10 times and the reactions were combined and diluted with 200 mL of EtOAc. The solids were removed by filtration and the EtOAc solution concentrated. The residue was taken up in a solution prepared from 80 mL of 30% aqueous NH3 and 800 mL of water. This was extracted with EtOAc (4×800 mL) then the combined extracts were dried with anhydrous Na2SO4, concentrated and purified by silica gel chromatography (PE:EtOAc=3:1) to give quinoline-3-carbonitrile (2-Im-10).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:10]=1.C(P(CCCC)CCCC)CCC.[CH2:37]([N:44]1[CH:48]=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:46](O)=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:37]([N:44]1[CH:48]=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:46]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:23])=[CH:14][C:15]=2[O:21][CH3:22])=[N:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1CO
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1OC
Reaction time: 15 h
Yield: 22.9 %

Procedure:
To a mixture of (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxyphenyl)methanol (1.04 g), tributylphosphine (1.34 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (0.81 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.67 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate as crystals (0.41 g, yield 23%) from a fraction eluted with tetrahydrofuran-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]([CH:10]([CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14])[CH3:9])=[O:7].C(N(CC)CC)C.[CH2:45]([NH2:49])[CH2:46][CH2:47][CH3:48].C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH2:45]([NH:49][C:13](=[O:14])[CH:12]=[CH:11][CH:10]([N:8]([C:6](=[O:7])[C:5]1[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:3]([C:2]([F:1])([F:37])[F:36])[CH:4]=1)[CH3:9])[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCCN
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)C(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 100 mg (0.19 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pent-2-enoic acid and 37 μl (0.27 mmol) of triethylamine in 3 ml of N,N-dimethylformamide at 0° C. is treated with 23 μl (0.23 mmol) of butylamine, followed by 38 μl (0.23 mmol) of diethyl cyanophosphonate. After stirring for 4 h at room temperature, the reaction mixture is concentrated, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution. The aqueous layer is further extracted with ethyl acetate (3×). The organic layers are combined, dried with sodium sulfate and concentrated. The residue is then purified by flash chromatography (95:5 methylene chloride/methanol) to give the title compound as a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.23.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCO)cc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
To a chilled (0° C.) solution of pentaethylene glycol (2.13 g, 8.92 mmol) in DCM (89 mL) were added TsCl (1.87 g, 9.81 mmol), Ag2O (3.10 g, 0.134 mmol), and KI (0.296 g, 1.78 mmol). After stirring for 20 min the reaction mixture was filtered through a 4 cm pad of celite and flushed with EtOAc. The resulted filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified via silica flash chromatography using 3:2 DCM/acetone as an eluent, providing 26 (2.63 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.20-4.11 (m, 2H), 3.76-3.54 (m, 18H), 2.44 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[OH:17].C[O-].[Na+].[C:21](OCC)(=[O:23])C.O>CO>[CH3:21][O:23][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[OH:17]
Reactant: Cc1cc2c(c(Br)c1O)C(C)(C)CCC2(C)C
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(O)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 89.57 %

Procedure:
To the solution of 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (12.8 g, 43.06 mmol) and sodium methoxide in methanol (5.0M) was added CuBr (1.24 g, 8.61 mmol) followed by ethyl acetate (2.5 mL). The reaction was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature then poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated to yield 1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (9.58 g, 89.57%). 1H NMR (CDCl3): δ 1.27 (s, 6H), 1.36 (s, 6H), 1.63-1.67 (m, 4H), 2.21 (s, 3H), 2.53 (s, 3H), 2.57 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 5.15 (d, 1H), 6.30 (s, 1H), 6.94 (s, 1H), 6.98 (s, 1H), 7.13 (d, 1H), 8.35 (s, 1H). APCI-MS m/z 532 (M+1).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][S:25]([CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:27])=[O:26].CN(C)C(N(C)C)=N>CS(C)=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][S:25]([CH3:24])(=[O:26])=[O:27])[CH2:35][CH2:34]3)[N:7]=1)=[N:9]2
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCS(C)(=O)=O)CC4)n3)nc2c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
To a solution of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 0.664 mmol) in DMSO (1.5 mL) under nitrogen was added 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (0.265 g, 0.996 mmol) and 1,1,3,3-tetramethylguanidine. The reaction was stirred at 80° C. for 18 h. After that time the reaction was cooled to rt, diluted with ethyl acetate (50 mL), washed with water (2×20 mL), brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 5,7-dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one (0.120 g, 38%) as a yellow solid: mp 243-244° C.; 1H NMR (400 MHz, CDCl3): δ 10.28 (br s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.73-7.66 (m, 1H), 6.87-6.81 (m, 2H), 6.49 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.69-3.61 (m, 4H), 3.23 (t, J=6.4 Hz, 2H), 3.09 (s, 3H), 2.98 (t, J=6.4 Hz, 2H), 2.72-2.64 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]([CH2:17]O)=[C:11]3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:27]>ClCCl>[Cl:27][CH2:17][C:16]1[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:9]=[N:10][C:11]=12
Reactant: COc1ccc(Cn2cnc3c(CO)cc(C(F)(F)F)nc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(CCl)cc(C(F)(F)F)nc32)cc1

Procedure:
[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x199 (0.55 g, 1.63 mmol) is dissolved in dichloromethane (20 ml). SOCl2 (2 ml) is added dropwise. The reaction mixture is refluxed for 1 h. The volatiles are rotary-evaporated. Then 50 ml of chloroform is additionally distilled off from the residue. The resulting chloroform solution is added dropwise at 0° C. under vigorous stirring to saturated aqueous NaHCO3. The organic phase is separated, dried with anhydrous sodium sulfate, evaporated, and dried under 1 mmHg for 1.5 h at 40° C. 7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine x202 (0.55 g, 95%) sufficiently pure for the next step is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (245 mg, 76%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([N:27]2[CH2:51][CH2:50][C:30]3([CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[CH:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:31]3)[CH2:29][CH2:28]2)[N:3]=1.[C:52]1([OH:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[CH:7]=[C:2]([O:58][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:3]=[C:4]([N:27]3[CH2:51][CH2:50][C:30]4([CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)=[O:36])[CH:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:31]4)[CH2:29][CH2:28]3)[N:5]=2)[C:10]([F:12])([F:11])[F:13])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(Cl)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CC2(CCN(c3nc(Oc4ccccc4)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (by-product from Step 3, Example 30a) (250 mg, 0.347 mmol) in 1,4-dioxane (9.0 mL) was added phenol (1.00 g, 10.6 mmol) and Cs2CO3 (3.65 g, 11.2 mmol). The reaction was heated at 80° C. for 12 h, then cooled to RT diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[CH2:4]1)[CH3:2].[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:1]([CH:3]1[C:8](=[O:9])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5](=[O:6])[CH2:4]1)[CH3:2]
Reactant: CCCCCCCCCBr
Reactant: CCC1CC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCN1C(=O)CC(CC)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-ethyl succinimide (4.72 mM) in dimethylformanide (10 ml) was treated with sodium hydride (5.20 mM) and nonyl bromide (5.20 mM). The reaction mixture was stirred at room temperature for two hours and then quenched with saturated aqueous ammonium chloride. The organic layer was separated and the aqueous layer extracted with ethyl acetate(3×25 ml). The combined organic layers were washed with 10% aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated in vacuo. Chromatography over silica gel afforded the desired product, pure 3-ethylN-nonyl succinimide.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1([NH:14][C:15]([C@@H:17]2[CH2:21][C@@H:20]([S:22]([C:25]3[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=3[Cl:32])(=[O:24])=[O:23])[CH2:19][C@H:18]2[C:33]([N:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)=[O:34])=[O:16])[CH2:13][CH2:12]1)#[N:10]>CN(C)C=O>[C:9]([C:11]1([NH:14][C:15]([C@@H:17]2[CH2:21][C@@H:20]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:27][C:26]=3[Cl:32])(=[O:23])=[O:24])[CH2:19][C@H:18]2[C:33]([N:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)=[O:34])=[O:16])[CH2:13][CH2:12]1)#[N:10]
Reactant: OCC(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
To a mixture of 2,2,2-trifluoroethanol (0.014 mL, 0.20 mmol) and sodium hydride (dispersion in oil, 55% w/w (9 mg, 20 mmol) in N,N-dimethylformamide (2 mL) was added (1R,2R,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amid (Example 119, 80 mg, 0.16 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 16 h, then was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with water and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol (98:2 v/v) as eluant to afford the title compound (32 mg, 31%) as an off-white gum. MS (EI): 570.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH3:24])[C:12]3=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2C1=O
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. overnight, then was cooled to ° C. and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf0.61.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)=[CH:15][C:14]=2[F:28])[CH2:11][C:10]([C:29]([C:35]([F:38])([F:37])[F:36])([C:31]([F:34])([F:33])[F:32])[OH:30])=[N:9]1.[CH3:39][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])([CH3:39])[CH3:26])=[CH:23][CH:24]=3)=[CH:15][C:14]=2[F:28])[CH2:11][C:10]([C:29]([C:35]([F:38])([F:37])[F:36])([C:31]([F:32])([F:33])[F:34])[OH:30])=[N:9]1
Reactant: CC(=O)c1ccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)cc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-(4′-acetyl-3-fluoro-biphenyl-4-yl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (10.0 mg, 0.02 mmol) prepared in Example 341 in tetrahydrofuran (1.0 mL), was slowly added methylmagnesium chloride (in 3.0 M tetrahydrofuran, 30.0 uL, 0.09 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 5 hours, quenched with a saturated solution of ammonium chloride at 0° C., and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:10]1[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([S:18](Cl)(=[O:20])=[O:19])[C:11]=1[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>C(#N)C>[C:3]([C:10]1[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([S:18]([NH2:2])(=[O:20])=[O:19])[C:11]=1[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)c1sc([N+](=O)[O-])c(S(=O)(=O)Cl)c1CNS(C)(=O)=O
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1sc([N+](=O)[O-])c(S(N)(=O)=O)c1CNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
Concentrated aqueous ammonium hydroxide solution (3 mL) was added to a solution of Boc-4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonyl chloride (3.30 g, 7.59 mmol) in acetonitrile (90 mL) at 0° C. The mixture was stirred at 0° C. for 45 min, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash column chromatography (Teledyne Isco RediSep column; 20-90% ethyl acetate in hexanes) afforded the desired product, Boc-4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (2.64 g, 6.35 mmol, 84%), as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.54 (9H, s), 3.35 (3H, s), 5.12 (2H, s), 5.81 (2H, bs), 7.61 (1H, s).