Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCC(OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC1CCC(C(=O)O)CC1

Procedure:
The ethyl 4-t-butoxycyclohexane-1-carboxylate (1 g), thus obtained, was heated on a steam bath with 2M sodium hydroxide solution (10 ml) to which had been added ethanol (2 ml). After about 4 hours a homogenous solution had formed. The reaction mixture was washed with petroleum ether (60-80) and the aqueous phase acidified with concentrated hydrochloric acid. An oil separated which crystallised on cooling and scratching. The solid was collected and recrystallised from petroleum ether (60-80) to yield 4-t-butoxycyclohexane-1-carboxylic acid, m.pt. 100°-105° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([CH2:15][OH:16])=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([CH:15]=[O:16])=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccc3ccccc3c12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc2ccc3ccccc3c12
Reaction time: 6 h

Procedure:
4-Phenanthrenemethanol (Aldrich, 29 g, 0.14 mol) was treated with pyridinium chlorochromate (PCC) (Aldrich, 45 g, 0.21 mol) in CH2Cl2 (2000 mL). After 6 h at RT, the reaction mixture was filtered through a plug of SiO2 to give after removal of solvent and drying and crystallization from CH3OH, 20.5 g (71%) of phenanthrene-4-carboxaldehyde mp 82.5°-84.5° (C, H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH3:11]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: N
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Bromophenylisothiocyanate (21.4 g) was dissolved in tetrahydrofuran (50 mL), and concentrated aqueous ammonia (28%) (13.7 mL) was added dropwise to the solution, followed by stirring at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, and the crystals were recovered through filtration by use of water, followed by recrystallization from ethanol, to thereby yield the title compound (16.4 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrCc1ccccc1
Product: O=C(O)/C(=N\OCc1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)hydroxyimino)acetate with benzyl bromide followed by hydrolysis of the ester to give 2-(2-tritylaminothiazol-4-yl)-2-((Z)-benzyloxyimino)acetic acid; n.m.r. in solvent C:-5.44(s, 2H); 6.69(s, 1H); 7.2-7.7(m, 20H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].CN(C)[CH:22]=[O:23].[OH-].[Na+]>O1CCCC1>[CH:22]([C:7]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:23]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of n-butyl lithium (56.0 ml, 140 mmol) in tetrahydrofuran (100 mL) at −78° C. was added a solution of 2-bromo-5-(trifluoromethyl)benzoic acid (17.9 g, 66.7 mmol) in tetrahydrofuran (100 mL) over 0.5 hour, at which time the solution turned dark red. After stirring for 1 hour, N,N-dimethylformamide (50 mL, 646 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature over 6 hours. The mixture was cooled to 0° C. and then a solution of 2 N sodium hydroxide (120 mL) was added. The mixture was extracted with ether (2×50 mL). The aqueous layer was separated and concentrated hydrochloric acid was added to it until the pH was acidic. The mixture was extracted with ethyl acetate (3×80 mL). The organic extracts were combined, dried with sodium sulfate, filtered, and concentrated. The residue was purified on Analogix® Intelliflash280™ (SiO2, 7-100% solvent A in hexanes, solvent A=3:1:0.1 hexane:ethyl aceate:acetic acid) over 1 hour to obtain the title compound (4.5 g, 20.6 mmol, 31% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.78 (br, 1H) 7.93 (d, J=8.48 Hz, 1H) 8.13-8.20 (m, 2H) 8.38 (br, 1H); MS (DCI/NH3) m/z 236 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10].CNC>CO>[C:19]([C:15]1[CH:16]=[C:17]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(C)(C=O)CO
Agent: CNC
Solvent: O
Solvent: CO
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 92 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 185 g (0.9 mol) of 2,6-di-t-butylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. and under the autogenous pressure of 20-30 bar for 10 h. Workup of the reaction mixture by distillation yields 238 g (92%) of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 126°-127° C.; melting point 75°-77° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CCOCC.O>CN(C=O)C.CCCCC>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:9][C:3]2[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cc(I)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCC
Product: COc1ccc(COc2cc(I)ccc2Cl)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A suspension of 300 g (1179 mmol) of 2-chloro-5-iodophenol, 184 g (1179 mmol) of 4-methoxybenzyl chloride and 195.5 g (1415 mmol) of anhydrous K2CO3 in 1.2 L of anhydrous DMF is stirred for 5 hours at 70° C. and then cooled to room temperature. The reaction medium is then poured into 3 L of a 2/1 ether/water mixture. The organic phase is washed with 2×1 L of water, dried over Na2SO4 and concentrated under reduced pressure, and the residue obtained is solidified in pentane. 406 g of 2-[(4-methoxybenzyl)oxy]-1-chloro-4-iodobenzene are thus obtained in the form of a beige-colored powder.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N[S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35])(=[O:24])=[O:23])CC>>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:2]([NH:1][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35])(=[O:23])=[O:24])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Product: CN(C)CCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
The title compound was prepared from L-Phe-NHCH2CH2NMe2 following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: Br[C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].[CH2:14]([SH:17])[CH2:15][SH:16]>CO>[S:16]1[C:2]2([CH2:7][C:6](=[O:8])[NH:5][C:3]2=[O:4])[S:17][CH2:14][CH2:15]1
Reactant: SCCS
Reactant: O=C1C=C(Br)C(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2(SCCS2)C(=O)N1
Yield: 41.2 %

Procedure:
To bromomaleimide (30 mg, 0.17 mmol) and sodium acetate (14 mg, 0.17 mmol) in methanol (6 mL) was added 1,2-ethanedithiol (17 μl 0.17 mmol). After five minutes solvent removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow powder (13 mg, 0.07 mmol) in 41% yield. δH (500 MHz, CDCl3) 8.39 (s, 1H, NH), 3.75-3.69 (m, 2H, HH-2 and HH-3), 3.60-3.53 (m, 2H, HH-2 and HH-3), 3.30 (s, 2H, H2-9); δc (125 MHz, CDCl3) 177.93 (C═O), 172.76 (C═O), 61.23 (C5), 43.12 (C9), 41.05 (C2 and C3); IR (solid, cm−1) 3290 (m), 1703 (m), 1629 (s); MS (ES−) m/z (relative intensity): 188 ([M−H], 100); Exact Mass Calcd for [C6H7NO2S2]−H requires m/z 187.9840 Found 187.9839 (ES−); m.p. 112-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Br.[NH2:25][C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: C[C@H](N)C(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Br
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (1.5 g, 0.0078 mol), methanol (20 mL, 0.4 mol), triethylamine (2 mL, 0.02 mol) and (S)-2-aminopropanamide hydrobromide (1.6 g, 0.0094 mol) and the reaction was heated at 50° C. overnight. The reaction mixture was cooled to room temperature wherein the product precipitated out. The precipitate was filtered and dried to yield the pure product as a yellow solid. MS m/z=262.2 (M+H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].CCN=C=NCCCN(C)C.[C:19]([OH:31])(=O)[CH2:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C(OC([N:39]1[CH2:42][CH:41]([NH2:43])[CH2:40]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:39]1[CH2:42][CH:41]([NH:43][C:19]([CH2:20][NH:21][C:22](=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:31])[CH2:40]1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1ccccc1)NC1CNC1

Procedure:
The title compound was prepared as a TFA salt from the EDCI coupling of hippuric acid (Fluka) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharm) followed by the de-protection of N-Boc by TFA using the procedures described in Example 1, steps D and E.
Reaction SMILES: Cl[O-:2].[Na+].ClCl.[I:6][C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10]>[OH-].[Na+].IC(F)(F)C(F)=C(F)F.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=C(C)C=1>[I:6][C:7]([F:14])([F:13])[C:8]1([F:12])[O:2][C:9]1([F:11])[F:10]
Reactant: [O-]Cl
Reactant: FC(F)=C(F)C(F)(F)I
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: ClCl
Agent: [Cl-]
Solvent: Cc1cccc(C)c1
Product: FC(F)(I)C1(F)OC1(F)F
Temperature: -10 °C

Procedure:
In a 1000-ml flask equipped with a stirring apparatus and a thermometer were charged 100 ml of m-xylene, 500 ml of a sodium hypochlorite aqueous solution having a 12% available chlorine content and containing 5.0 g of sodium hydroxide, 20.0 g (77.5 mmols) of 3-iodopentafluoropropene and 0.25 g (0.6 mmol) of TOMAC as a catalyst. After the reaction liquid was cooled to -10° C., the reaction liquid was stirred with the stirring apparatus to initiate the reaction. The reaction was continued while maitaining the reaction temperature at -10° C. After the 15 minutes of reaction time lapsed, the conversion of 3-iodopentafluoropropene became almost 100%. Then the reaction liquid was cooled to -30° C. to freeze the aqueous phase, and the organic phase was separated therefrom. After the organic phase was dried over anhydrous sodium sulfate, the product was isolated from the organic phase through fractional distillation twice. Thus, 8.7 g (yield, 41%) of the captioned compound having a boiling point of 52° C. was obtained.
Reaction SMILES: Br.[NH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[NH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC1C(=O)Nc2ccccc2SC1c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)C(c2ccccc2)Sc2ccccc21
Temperature: 50 °C
Yield: 76.1 %

Procedure:
4.8 g of 3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide was dissolved in 80 ml of N,N-dimethylformamide. After the addition of 1.2 g of sodium hydride (in the form of a 60% suspension in oil), the resulting mixture was stirred at 50° C. for an hour. Then, a solution of 2.7 g of t-butyl bromoacetate in 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 50° C. for an additional hour. After the solvent was distilled off under reduced pressure, hexane was added to the residue so as to cause crystallization. The product was separated by filtration and washed with ether, with water and then with ether to obtain 4.0 g of the desired compound. This compound had a melting point of 178°-180° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])[N:13]=[C:7]2[CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O.CO>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[C:12]1[N:13]=[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][N:8]2[CH:11]=1
Reactant: COC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (1.2 g, 3.6 mmol) in THF (9.9 mL), water (9.9 mL) and methanol (2.2 mL) was added lithium hydroxide monohydrate (302 mg, 7.2 mmol) and the resulting mixture stirred vigorously overnight. The mixture was then evaporated and acidified with hydrochloric acid (1 N) and then extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow solid. Purification by trituration with heptane afforded the title compound (764 mg, 66%) which was obtained as a yellow solid. MS: m/e=318.1 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25](O)=[O:26])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:61]1([CH2:66][CH2:67][NH2:68])[CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([NH:68][CH2:67][CH2:66][N:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.4 g, 3.79 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was added HATU (1.729 g, 4.55 mmol) and DIPEA (1.655 mL, 9.48 mmol), the resulting mixture was stirred at r.t. for 30 min. Then 2-(pyrrolidin-1-yl)ethanamine (0.656 mL, 4.17 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The reaction mixture was concentrated and the residue was dissolved in DCM and washed with water, sat. NaHCO3 (aq.) and brine. The organic layer was separated and concentrated, the residue was purified by normal phase silica gel chromatography (CombiFlash), eluting with MeOH/DCM (0-20%) to afford 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (1 g, 2.148 mmol, 56.7% yield) as a yellow solid. LCMS: (M+H)+: 466.3.
Reaction SMILES: [CH:1]1([CH:7]([O:40][CH3:41])[C:8]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:9]=2[CH2:10][N:11]([CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:12]2[N:13]=[N:14][NH:15][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].C(=O)([O-])[O-].[Na+].[Na+]>CC1OCCC1.CN(C=O)C>[CH:1]1([CH:7]([O:40][CH3:41])[C:8]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:9]=2[CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[C:12]2[N:13]=[N:14][N:15]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO[Si](C)(C)C(C)(C)C)n1)C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine (40.4 mg, 0.068 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (25 mg, 22 μL, 0.10 mmol) in 2-MeTHF/DMF was added sodium carbonate (29.1 mg, 0.275 mmol). The slurry was stirred at 60° C. overnight. The reaction was diluted and filtered. The filtrate was concentrated and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in heptane) to afford the title compound (39.3 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H) 0.80 (s, 9H) 0.92-1.12 (m, 5H) 1.15-1.21 (m, 1H) 1.42-1.52 (m, 1H) 1.57-1.62 (m, 2H) 1.68-1.72 (m, J=2.90 Hz, 1H) 1.89 (d, J=12.44 Hz, 1H) 3.03 (s, 3H) 4.05-4.09 (m, 3H) 4.54 (t, J=5.60 Hz, 2H) 4.64-4.76 (m, 3H) 4.89 (d, J=16.17 Hz, 1H) 7.35 (s, 1H) 7.47 (d, J=7.88 Hz, 1H) 7.54 (d, J=9.12 Hz, 1H) 7.65 (s, 2H) 7.75 (s, 1H). MS (ES+) Calc: 753.3, Found: 754.6 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([O:21]CC2C=CC=CC=2)[CH:20]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:3]>[Pd].C(O)C.C1COCC1>[OH:21][C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:20]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
10% Palladium on charcoal (550 mg) was added to a solution of 3-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide (5.5 g, 14.6 mmol) in ethanol (75 mL) and THF (50 mL) and the mixture stirred at RT under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration and the filtrates evaporated in vacuo to a residue which was crystallised from ethyl acetate to give the desired compound (3.42 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:13]12[O:18][CH:16]([CH2:15][CH2:14]1)[CH2:17][N:11]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]3[N:8]([CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[N:9]=[CH:10][C:5]=13)[CH2:12]2
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CN(C)CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Yield: 100.8 %

Procedure:
To 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1 g, 3.8 mmol), 2-(dimethylamino)ethanol (0.57 mL, 5.7 mmol) triphenylphosphine (1.5 g, 5.7 mmol) in THF (25 mL) is added DIAD (1.1 mL, 5.7 mmol) in drops over 5 min. After 2 h the mixture is concentrated in vacuo, diluted with ether and extracted with 1N aq HCl (2×). The aqueous layers are neutralized with NaOH and extracted with CH2Cl2. The organic layers are treated with 4N HCl in dioxane and concentrated in vacuo. The resulting solid was triturated with ether. Material from a reaction conducted with 0.37 g of pyrazolopyrimidine was combined with this material to give 1.29 g of 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylethanamine as a solid. This material (0.5 g, 1.34 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.44 g, 2.0 mmol), aq. Na2CO3 (1.84 mL, 2M), and tetrakis triphenylphosphine palladium (50 mg) in 1:1 toluene:ethanol (10 mL). The reaction mixture was heated in a microwave at 12° C. for 60 min. The reaction was repeated. The combined reaction mixtures were diluted with EtOAc and filtered to give a solid (0.51 g). The aq. Phase was washed with EtOAc and the combined organic layers concentrated in vacuo. Trituration of the residue gave a solid (0.28 g). The precipitates were combined to give 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-(dimethylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a solid (0.79 g). A solution of this material (550 mg, 1.4 mmol) and triethylamine (1.05 mL) in dichloromethane was treated with triphosgene (208 mg, 0.7 mmol). After 30 min one eleventh of the solution was treated with excess methylamine (2N in THF). Reverse phase HPLC gave the title compound (39 mg) MS m/s=451.2 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[C:29]([CH3:30])=[C:28]([CH:31]=O)[C:27]([CH3:33])=[N:26]4)=[CH:21][C:20]=3[CH3:34])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.Cl.[NH2:40][OH:41].N1C=CC=CC=1>O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[C:29]([CH3:30])=[C:28]([CH:31]=[N:40][OH:41])[C:27]([CH3:33])=[N:26]3)=[CH:21][C:20]=2[CH3:34])[CH2:2][CH2:3]1
Reactant: NO
Reactant: Cc1cc(-n2nc(C)c(C=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(-n2nc(C)c(C=NO)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Yield: 79.7 %

Procedure:
At room temperature, a mixture of 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-4-formyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 51) 1.7 g, chloroform 20 ml, hydroxylamine hydrochloride salt 0.3 g and pyridine 0.9 g was stirred for twelve hours. To the resulting mixture was added water 20 ml, and the mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and then was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3,5-dimethyl-1H-pyrazole-4-carbaldehyde oxime 1.4 g.