Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:5]([O:32][SiH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:19]([CH2:20][NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[CH:18][N:17]=[C:16]([S:30][CH3:31])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)(C)(C)C.C(N(CC)CC)C.[C:53](Cl)(Cl)=[O:54].[C:57]1([CH3:63])[CH:62]=CC=C[CH:58]=1>>[Si:33]([O:32][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:14]3=[N:15][C:16]([S:30][CH3:31])=[N:17][CH:18]=[C:19]3[CH2:20][N:21]([C:22]3[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=3[Cl:28])[C:53]2=[O:54])[CH:10]=[CH:11][CH:12]=1)([C:57]([CH3:63])([CH3:62])[CH3:58])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CC(O[SiH](c3ccccc3)c3ccccc3)C(C)(C)C)c2)n1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(c1cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(=O)N(c1c(Cl)cccc1Cl)C2

Procedure:
A solution containing 1.35 g (2 mmol) of 4-[3-(2-tertbutyldiphenylsilyloxyethyl)phenyl]amino-5-(2,6-dichloroanilino)methyl-2-methylthiopyrimidine and 0.85 ml (6 mmol) of triethylamine in 5 ml of anhydrous toluene was added dropwise to 3.2 ml (6 mmol) of a 20% solution of phosgene in toluene dissolved in 10 ml of toluene at 0° C. under an atmosphere of nitrogen. The reaction was then heated at reflux for 6 hours then evaporated. The residue was partitioned between ethyl acetate (40 ml) and 2M hydrochloric acid (40 ml) and the ethyl acetate layer separated, washed with saturated aqueous sodium bicarbonate (40 ml ), dried over magnesium sulfate, filtered and evaporated to give 1.5 g of 1-[3-(2-t-butyldiphenylsilyloxyethyl)phenyl]-3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow gum. [Mass spectrum (ESI) MH+ =699].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[CH2:24][CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27]CC)(=[O:3])[CH3:2].[N:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1.[Si](Br)(C)(C)C>CC#N>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[CH2:24][CH2:25][P:26](=[O:27])([O-:30])[O-:33])(=[O:3])[CH3:2].[CH2:35]([NH+:34]([CH2:31][CH3:32])[CH2:39][CH3:38])[CH3:36].[CH2:35]([NH+:34]([CH2:31][CH3:32])[CH2:39][CH3:38])[CH3:36]
Reactant: CCOP(=O)(CC[C@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)OCC
Reactant: c1ccncc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@H](CCP(=O)([O-])[O-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: CC[NH+](CC)CC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 5a (260 mg, 0.53 mmol) in CH3CN (5 mL) at 0° C., pyridine (450 μL, 5.52 mmol, 10.5 equiv.) was added, followed by Me3SiBr (730 μL, 5.52 mmol, 10.5 equiv.). The solution was stirred at 0° C. for 3 h. The reaction was quenched with H2O/C5H5N (9:1, 5 mL) and the solution was evaporated to dryness. The residue was purified by Purification Method 1 (0-50% MeOH against 0.05 M TEAB) to afford the triethylammonium salt of phosphonic acid 6 in quantitative yield (230 mg, 0.52 mmol): Rf 0.1 (EtOAc/EtOH 20:1); δH (400 MHz, CDCl3) 5.25 (dd, 1H, J5,6 and J6,7 2.4 Hz, H-6), 5.15-5.05 (m, 2H, H-4, H-5), 4.14-3.95 (m, 4H, H-3, H-7, H-8a, H-8b), 2.98 (q, 6H, J 7.3 Hz, NCH2CH3), 1.85-1.30 (m, 4H, H-1a, H-1b, H-2a, H-2b), 1.06 (t, 7.6H, J 7.3 Hz, NCH2CH3); δC (100 MHz, CDCl3) 72.3 (d, JC,P 14.3 Hz, C-3), 68.4, 68.3, 68.2 (C-4/C-5/C-6/C-7), 62.0 (C-8), 46.7 (NCH2CH3), 22.5 (d, JC,P 136.4 Hz, C-1), 20.2, 20.0 (4×C(O)CH3), 19.3 (C-2), 8.3 (NCH2CH3). m/z (ESI) 439.0999 [M−H]−, C16H24O12P requires 439.1011.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:37]([CH3:38])[CH2:36][CH2:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1cccc(Cl)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>[Ag]=O.CN(C=O)C>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1cccc(CO)[nH]1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of 1.38 g of 6-(hydroxymethyl)pyridin-2(1H)-one, 2.15 g of tert-butyl bromoacetate, 3.07 g of silver oxide, and 33 mL of DMF was stirred at room temperature for 12 hours, and then at 60° C. for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.92 g of tert-butyl {[6-(hydroxymethyl)pyridin-2-yl]oxy}acetate as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[OH-].[Na+]>Cl.O1CCOCC1.O>[CH3:1][O:2][CH:3]1[CH:8]([NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC1CNCCC1NC(=O)c1ccccc1

Procedure:
To a solution of 1,1-dimethylethyl 3-(methyloxy)-4-[(phenylcarbonyl)amino]-1-piperidinecarboxylate D20 (4.0 g) in HCl/1,4-dioxane (30 ml) was stirred at room temperature for overnight. The resulting mixture was dissolved in water (50 ml) and basified with sodium hydroxide to pH 10.0 then extracted with DCM (3×100 ml). The organic layer was dried over anhydrous MgSO4, concentrated in vacuo to desired product D21 as an oil in 500 mg. LCMS [MH+] 235@1.17 and 1.19 (isomers) (5 min run)
Reaction SMILES: [CH3:1][CH:2]([NH2:13])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH:2]([NH:13][CH:19]2[CH2:18][CH2:17][C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([N:15]([CH3:29])[CH3:14])[CH2:21][CH2:20]2)[CH3:1])=[CH:5]1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
DL-α-Methyltryptamine (348 mg, 2 mmol) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (229 μl), the mixture was stirred for one hour at RT. Sodium triacetoxyborohydride (550 mg) was then added and the suspension was stirred for four days at RT. For working up, water (15 ml) was added to the reaction mixture. The clear phases were separated and the aqueous phase was washed with ether (10 ml) and then rendered strongly alkaline with sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (4×10 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (723 mg) was recrystallized twice from a mixture of ethyl acetate/cyclohexane (2 ml/6 ml). A fraction of the nonpolar diastereoisomer of N′-[2-(1H-indol-3-yl)-1-methyl-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (128 mg, m.p. 155-162° C.) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([OH:10])=[C:4]([CH2:11]O)[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>C(O)(=O)C.OS(O)(=O)=O>[Cl:13][C:14]1[C:15]([OH:21])=[C:16]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([CH2:8][C:16]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[C:15]=2[OH:21])[C:5]=1[OH:10]
Reactant: OCc1cc(F)cc(CO)c1O
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1c(Cl)cc(Cl)cc1Cc1cc(F)cc(Cc2cc(Cl)cc(Cl)c2O)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-fluoro-2,6-bis(hydroxymethyl)phenol (2.0 g) was dissolved in glacial acetic acid (20 ml) and added slowly to 2,4-dichlorophenol (3.8 g) in concentrated H2SO4 at 60°-70°. The mixture was held at 65°-70° for 1 hr, cooled, acetic acid (20 ml) was added to dissolve the solids and the solution was poured into ice-water. The solid precipitate was purified by column chromatography over silica gel using hexane-ethyl acetate as eluent. The title compound was obtained in yield of 1.3 g, mp 168°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>[Ag].CN(C)C=O>[N:17]1([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1c[nH]cn1
Agent: [Ag]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1

Procedure:
A mixture of 0.1 mole of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione and 0.1 mole of the silver salt of imidazole were heated in 300 ml. of dimethylformamide for 8 hours. The reaction mixture was concentrated to remove the solvent and the residue was boiled with 200 ml. of toluene and filtered to remove the insoluble material. The toluene layer was concentrated and the desired product was purified by HPLC using ethyl acetate and a silica gel column.
Reaction SMILES: C12(COC3C=CC(C(N)=O)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:53][CH2:52]4)=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.CS(Cl)(=O)=O.[CH:60]1([S:64](Cl)(=[O:66])=[O:65])[CH2:63][CH2:62][CH2:61]1>>[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:52][CH2:53]4)=[CH:49][C:45]([C:46]([NH:48][S:64]([CH:60]4[CH2:63][CH2:62][CH2:61]4)(=[O:66])=[O:65])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: O=S(=O)(Cl)C1CCC1
Agent: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)C1CCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with cyclobutanesulfonyl chloride, the title compound was obtained as a colorless solid (0.05 g, 10%): 1H NMR (300 MHz, CDCl3) δ8.57-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.61-6.48 (m, 1H), 4.61-4.46 (m, 1H), 3.55 (s, 2H), 2.74-2.56 (m, 2H), 2.45-2.29 (m, 2H), 2.12-1.97 (m, 6H), 1.84-1.64 (m, 12H), 0.99-0.88 (m, 2H), 0.71-0.58 (m, 2H); MS (ES+) m/z 462.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=O)[S:5][C:6]=1[CH3:7].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([CH:8]=[N:11][OH:12])[S:5][C:6]=1[CH3:7]
Reactant: NO
Reactant: Cc1nc(C=O)sc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C=NO)sc1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4,5-dimethylthiazole-2-carbaldehyde (987 mg, 7.0 mmol) in 1,4-dioxane (35 mL) was added hydroxylamine hydrochloride (1.45 g, 21 mmol) and K2CO3 (3.8 g, 28 mmol). The resulting mixture was stirred at 100° C. for 2 hours and then diluted with EtOAc (150 mL), washed with H2O (30 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was used for next step without further purification. LCMS m/z (M+H) 157.1 found, 157.1 required.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:26]([F:29])([F:28])[F:27])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:5])C.C1COCC1.CCO.O.O[Li].O.Cl>O>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:11]=1)[O:8][CH:7]([C:26]([F:28])([F:29])[F:27])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3cccc(F)c3)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)cc(C#Cc3cccc(F)c3)c2OC1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To 0.440 g (1.036 mmole) of ethyl-6-Chloro-8-[(3-fluorophenyl)ethynyl]-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 5.2 mL of a solvent mixture of THF/EtOH/H2O (7:2:1) followed by 65 mg (1.55 mmole) of LiOH—H2O. The mixture was stirred at 60° C. for two hours. The mixture was concd, diluted with water and acidified with 0.5N HCl. The crude material was purified using reverse phase chromatography to afford 0.387 g (94%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 5.79 (q, 1H, J=6.4 Hz), 7.04-7.09 (m, 1H), 7.21-7.23 (m, 2H), 7.31-7.33 (m, 2H), 7.50 (d, 1H, J=2.4 Hz), 7.84 (s, 1H); MS (ES+) 397 (M+1, 100); HRMS (ES−) m/z calcd for (C19H9O3ClF4) 395.0093, found 395.0092.
Reaction SMILES: C1O[CH:4]([C:5]2[C:6]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[N:7][N:8](C(OC)=O)[CH:9]=2)[O:3]C1.N1CCCCC1>O1CCOCC1.O>[N+:19]([C:16]1[O:15][C:14]([C:6]2[C:5]([CH:4]=[O:3])=[CH:9][NH:8][N:7]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: COC(=O)n1cc(C2OCCO2)c(-c2ccc([N+](=O)[O-])o2)n1
Solvent: C1CCNCC1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1

Procedure:
React 3.1 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethyleneacetal in 50 ml of dioxan and 25 ml of water with 1.73 g of piperidine for 20 minutes at room temperature (20° C) and then proceed according to the method of part (a) above to obtain 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde with a melting point of 185° to 187° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:12])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(Oc2ccccc2)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred solution of 3-phenoxybenzaldehyde (2 g, 10.09 mmol) in THF (15 mL) at −78° C. was added phenyllithium (6.73 mL, 1.8M solution in cyclohexane-ether) dropwise. After stirring under argon at −78° C. for 4 hrs, the reaction was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (10%/90%) to (20%/80%)) to give 128 (2.79 g, 86% yield): 1H-NMR (400 MHz, chloroform-d) δ 6.87-7.38 (m, 10 H), 7.09 (m, 1 H), 6.99 (app d, J=7.3 Hz, 1 H), 6.88 (m, J=8.6, 2.2 Hz, 1 H), 5.81 (s, 4 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:13])[NH2:12])([CH3:10])[CH3:9])(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH2:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of (1-carbamoyl-1-methyl-ethyl)-carbamic acid tert-butyl ester (945 mg, 4.67 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10.0 mL, 64 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated in vacuo to afford 882 mg of the title compound as a white solid, isolated as the TFA salt, m/z 103.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>C(O)C>[OH:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[C:15]([S:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (102 mg, 0.570 mmol) was reacted in ethanol (2 mL) with the product from Example 34b (161 mg, 0.560 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (50 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H) 2.12 (s, 3H) 2.75 (s, 3H) 6.31 (d, J=6.99 Hz, 1H) 6.61 (s, 1H) 7.15 (s, 1H) 7.29 (d, J=8.46 Hz, 2H) 7.56 (d, J=8.82 Hz, 2H) 7.77 (d, J=8.82 Hz, 1H) 8.39 (d, J=5.52 Hz, 1H) 8.96 (d, J=8.82 Hz, 1H) 9.90 (s, 1H) 10.08 (s, 1H) 10.84 (s, 1H) 14.24 (br s, 1H); MS (ESI+) m/z 431 (M+H)+.
Reaction SMILES: [C:1]1(=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[K+]>CS(C)=O>[N+:13]([CH2:16][C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1
Yield: 89.4 %

Procedure:
16.8 g (0.1 mole) Ethyl cyclohexylideneacetate, 9.2 g, (0.15 mole) nitromethane and 0.64 g (0.01 mole) potassium hydroxide (content 88%) in 40 mL dimethyl sulphoxide are stirred for 2 hours at 100° C. The reaction mixture is worked up analogously to Example 2 to give 20.5 g ethyl 1-nitromethyl-1-cyclohexaneacetate (89.4% of theory). According to GC., the content is 82.8% and 10.2% of starting compound and 4.1% of by-product are obtained (see Example 3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:27][C:24]1[CH:25]=[N:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:22][CH:23]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)CCOc1ccc(N)cn1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 73.8 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (5.0 g, 18.0 mmol) was reacted with 6-(2-(dimethylamino)ethoxy)pyridin-3-amine (3.5 g, 19.0 mmol) to afford the desired product (5.7 g, 82%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 11.90 (s, 1H), 9.12 (s, 1H), 8.08-7.98 (m, 1H), 7.87-7.76 (m, 1H), 7.74-7.63 (m, 2H), 7.33 (dd, J=8.8, 2.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.44 (t, J=5.5 Hz, 2H), 2.78 (s, 3H), 2.74 (t, J=8.8 Hz, 2H), 2.36 (s, 6H).
Reaction SMILES: C(O[CH2:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([Br:19])[N:13]=2)C1C=CC=CC=1.B(Br)(Br)[Br:21]>C([O-])(O)=O.[Na+]>[Br:19][C:14]1[N:13]=[C:12]2[S:11][C:10]([CH2:9][Br:21])=[N:18][C:17]2=[CH:16][CH:15]=1
Reactant: Brc1ccc2nc(COCc3ccccc3)sc2n1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: BrCc1nc2ccc(Br)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.1 %

Procedure:
A solution of 2-Benzyloxymethyl-5-bromo-thiazolo[5,4-b]pyridine (1.60 g, 4.77 mmol) DCM (15 mL) was cooled to −78° C. followed by addition of BBr3 (2.27 ml, 23.86 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (2.0 g, Crude yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CON(C)C(=O)c1ccc(C)cc1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CC(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Under an argon atmosphere, a solution of 10.40 g of N-methoxy-N-methyl-p-toluamide in 100 ml of tetrahydrofuran was ice-cooled and 4-methylbenzylmagnesium chloride (solution prepared by dissolving 10.60 g of α-chloro-p-xylene and 1.94 g of magnesium in 85 ml of tetrahydrofuran) was added dropwise. After stirring for one hour, 100 ml of 10% hydrochloric acid was slowly added. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the crude crystal was washed with diisopropyl ether and then dried under reduced pressure to obtain 8.43 g of the desired compound as a colorless crystal having a melting point of 93 to 100° C.