Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[OH-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Yield: 51.9 %

Procedure:
To a solution of 3-nitroaniline (0.5 g, 3.6 mmol) in 10 ml acetic acid added bromine (0.2 ml, 4.0 mmol) and stirred at 0° C. for 1 hour. The solution was filtered after recovering to room temperature to obtain 2-bromo-5-nitrobenzenamine (0.32 g, 40%) as a powder. A solution of 2-bromo-5-nitrobenzenamine (0.4 g, 1.8 mmol), sodium hydroxide (0.14 g, 3.6 mmol) and benzoyl chloride (0.24 ml, 2.0 mmol) in 20 ml THF was stirred for 2 hours in icy water bath. The reaction was quenched and washed with water (3×20 ml). The mixture was dried over anhydrous sodium sulfate. The crude N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 50%) was obtained after evaporation of the solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (m, 2H), 7.68 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.7 Hz, 1H), 8.00 (m, 2H), 8.62 (s, 1H), 9.55 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[N:13]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[N:13]=1
Reactant: CCOC(=O)c1cn2nc(OCc3cc(OC)c(OC)c(OC)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(COc2ccc3nc(C(=O)O)cn3n2)cc(OC)c1OC
Yield: 83.5 %

Procedure:
The product of stage (a) (1.94 g, 5 mmol) was heated under reflux with stirring with sodium hydroxide solution (1 ml, 10M, 10 mmol), water (9 ml) and methanol (5 ml) for 20 min. The mixture was cooled and acidified with dilute hydrochloric acid and filtered to give a solid which was dried at 60° in vacuo to give the title compound as a powder (1.5 g), m.p. 224°-226° (decomp), Nmr δH (d6 -DMSO) 8.56 (1H,s,3H), 8.07 (1H,JAB 8.8 Hz, 8H), 7.05 (1H, JAB 8.8 Hz, 7H) 6.88 (2H,s,ArH), 5.29 (2H,s,CH2Ar), 3.82 (6H, s, OCH3)3.68 (3H, s, OCH3) and 3.32 (1H, br.s, CO2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4].[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][CH:24]1[C:30]([OH:32])=[O:31])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>CC#N>[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:28])([F:29])[CH2:25][CH:24]1[C:30]([O:32][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4])=[O:31])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Yield: 83 %

Procedure:
2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone (1 g, 3.07 mmol) and 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (849 mg, 3.38 mmol) were suspended in MeCN (15 mL) and treated with Et3N (0.45 mL, 3.22 mmol). After stirring o/n, the reaction mixture was concentrated. The resulting residue was dissolved in EtOAc and washed with water, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (0% to 20% EtOAc/Hex) to provide the title compound (1.27 g, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.CN(C(ON1N=N[C:45]2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:59]([O:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66]C2CCNCC2)=[CH:64][CH:63]=1)[CH3:60]>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([C:21]([CH:46]4[CH2:45][CH2:44][N:49]([CH2:66][C:65]5[CH:73]=[CH:74][C:62]([O:61][CH2:59][CH3:60])=[CH:63][CH:64]=5)[CH2:48][CH2:47]4)=[O:23])=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[CH:26][CH:27]=1)#[N:2]
Reactant: N#Cc1ccc(CN2CCC(NC(=O)c3ccc(C(=O)O)cc3)CC2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOc1ccc(CC2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(CN2CCC(C(=O)c3ccc(C(=O)NC4CCN(Cc5ccc(C#N)cc5)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 450.7 %

Procedure:
To a stirred mixture of 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoic acid (100 mg, 0.275 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added triethylamine (84 μl, 0.825 mmol), HATU (115 mg, 0.3 mmol), and 4-(4-ethoxybenzyl)piperidine (61 mg, 0.275 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration, purified by column chromatography to yield 0.7 g (55%) of N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(1-(4-ethoxybenzyl)piperidine-4-carbonyl)benzamide (compound 27) as an off-white solid. 1H-NMR (CDCl3, 300 MHz): δ 7.761 (d, 2H), 7.600 (m, 2H), 7.434 (m, 4H), 7.022 (d, 2H), 6.812 (d, 2H), 6.022 (d, 1H), 4.658 (m, 1H), 3.994 (dd, 2H), 3.569 (m, 3H), 2.885 (m, 4H), 2.505 (m, 2H), 2.227 (m, 2H), 2.049 (m, 2H), 1.639 (m, 6H), 1.405 (m, 3H); LCMS (m/z): 565 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1F)#[N:2].O.[NH2:14][NH2:15]>C(O)CCC>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: NN
Reactant: N#Cc1ccc(C(=O)O)cc1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 110 °C
Yield: 26.3 %

Procedure:
To a solution of 4-cyano-3-fluorobenzoic acid (500 mg, 3.0 mmol) in n-butanol (9 mL) was added hydrazine monohydrate (0.5 mL, 10 mmol). The reaction was heated to 110° C. overnight. The reaction was cooled to room temperature and the precipitate was collected by filtration. The solid was then dissolved in 1 N aqueous sodium hydroxide (2 mL) and extracted with ethyl acetate (2×). The aqueous layer was acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to provide the title compound (140 mg, 26%) as a red solid. +ESI (M+H) 178.2; 1H NMR (400 MHz, CD3OD, δ): 7.99-8.01 (m, 1H), 7.73 (dd, J=8.4, 0.8 Hz, 1H), 7.61 (dd, J=8.5, 1.3 Hz, 1H).
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1>>[N:21]1[CH:20]=[CH:25][CH:24]=[C:23]([O:26][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:22]=1
Reactant: BrC1=NOCC1
Reactant: Oc1ccc(Br)nc1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-216a and I-216b were prepared in 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 2-bromo-5-hydroxypyridine using Method 5 to provide racemic compound I-216. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=389.1 m/z. Activity: B
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O.[ClH:29]>C(O)(=O)C.O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH2:8]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)C(C)C
Reaction time: 0.08 h

Procedure:
29.6 g of t-butoxycarbonylvalyltyrosine methyl ester is dissolved in 255 ml of acetic acid. To this solution is added 128 ml of 6 N hydrochloric acid in dioxane. The reaction is allowed to stand for five minutes and the solution is removed under vacuum. The residue is triturated with ethyl ether. The resultant precipitate is filtered, washed with ethyl ether and dried in a vacuum oven at 55° C. to afford valyltyrosine methyl ester hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:8]=[CH:7]2)([O-:3])=[O:2].[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2CCCCc2ccccc2)c1
Product: O=[N+]([O-])c1ccc2nn(CCCCc3ccccc3)cc2c1
Temperature: 120 °C

Procedure:
A suspension of 5-nitroindazole (1.098 g, 0.006731 mol), 1-bromo-4-phenylbutane (1.52 g, 0.00713 mol) and cesium carbonate (2.70 g, 0.00829 mol) in N,N-dimethylformamide (15 mL) was degassed with Ar for 10 min and then heated at 120° C. in a microwave for 50 min. The reaction was poured into water and extracted with methylene chloride (3×). The combined organics were washed with water and brine and then dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the two regioisomers 5-nitro-1-(4-phenylbutyl)-1H-indazole and 5-nitro-2-(4-phenylbutyl)-2H-indazole as an inseparable mixture.
Reaction SMILES: C[O:2][C:3]([C:5]1([F:25])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=O.[NH3:26]>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:5]([F:25])([C:3]([NH2:26])=[O:2])[CH:6]=[C:7]3[N:11]([CH3:12])[CH2:10][N:9]=[C:8]3[CH:13]=2)=[C:17]([F:24])[CH:18]=1)[CH3:23]
Reactant: CCc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(=O)OC)c(F)c1
Reactant: N
Product: CCc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(N)=O)c(F)c1
Yield: 65 %

Procedure:
A solution of 6-(4-Ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (0.309 g) in ammonia-saturated isopropanol (10 mL) was heated in a sealed pressure tube at 80° C. for 80 h. The resultant reaction mixture was concentrated to dryness and recrystallized from ethanol to afford pure 6-(4-ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid amide (0.199 g, 65% yield): m.p. 249–251° C.; 1H NMR (400 MHz, acetone-d6) δ 8.45 (brs, 1 H), 8.18 (s, 1 H), 5.94 (s, 1 H), 5.59 (br s, 1 H), 6.95 (dd, J=12.5, 2.0 Hz, 1 H), 6.89 (br s, 1 H), 6.81 (br d, 1 H), 6.56 (td, J=8.6, 4.9 Hz, 1 H), 3.95 (s, 3 H), 2.54 (q, J=5.6 Hz, 2 H), 1.16 (t, J=5.6 Hz, 3 H). Anal. Calcd/Found for C15H16F2N4O: C, 61.64/61.26; H, 4.88/4.84; N, 16.96, 16.68; F, 11.50/11.85.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:30])([F:29])[F:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(-c2ccccc2C(F)(F)F)n2c1c(C)nc1ccc(F)cc12
Yield: 49 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-trifluoromethylphenylboronic acid (58 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (44 mg, 49% yield). EIMS 360.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[C:3]=1[O:10][CH3:11].[N+:12]([O-])(O)=O>S(=O)(=O)(O)O.C(O)C.[Pd]>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:10][CH3:11])=[CH:2][C:7]=1[NH2:12]
Reactant: O=[N+]([O-])O
Reactant: COc1c(Br)cc(F)cc1Br
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc(F)c(N)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[Cl:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>C(#N)C>[Cl:7][CH2:8][CH2:9][C:10]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:11]
Reactant: COC(=O)NN
Reactant: O=C(Cl)CCCl
Solvent: CC#N
Product: COC(=O)NNC(=O)CCCl
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 45 g. (0.5 moles) of methyl carbazate in 375 ml. of acetonitrile 63.5 g. (0.5 moles) of 3-chloro-propionyl chloride are added dropwise. The reaction mixture is heated to boiling for 16 hours, clarified and cooled. The precipitated crystals are filtered. Thus 70.5 g. of the desired compound are obtained in the form of white crystals. Yield 78.3%. M.p.: 129° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][O:21]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][OH:21]
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1COC(C)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1CO)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was added potassium carbonate (560 mg, 4.0 mmol) at room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (150 mL), washed with 1.0 M aqueous hydrogen chloride and dried (Na2SO4) to give the pure 3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in almost quantitative yield. To the alcohol (800 mg, 1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0° C. and then brought to room temperature. After 1 h, the reaction mixture was washed with aqueous sodium hydrogencarbonate, dried (Na2SO4). The solvent was removed, dissolved the crude product in anhydrous THF (20 mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL) in a sealed tube. The sealed tube was heated at 80° C. for a period of 12 h and then removed the solvent. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid tert-butyl ester in 39% overall yield. 1H NMR (500 MHz, CDCl3): in δ 7.40-7.31 (m, 5H), 7.01-7.00 (m, 1H), 6.83-6.82 (m, 1H), 6.66 (s, 1H), 5.91-5.90 (m, 1H), 5.13-5.01 (m, 4H), 3.50-3.46 (m, 1H), 3.03 (s, 3H), 2.85-2.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].Cl.[F:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[CH:19][C:18]=1[NH:25][NH2:26]>O>[Cl:23][C:21]1[C:20]([OH:24])=[CH:19][C:18]([NH:25][N:26]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:17]([F:16])[CH:22]=1
Reactant: NNc1cc(O)c(Cl)cc1F
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 82.9 %

Procedure:
Then, 49.2 g of sodium acetate and 40.5 g of 1,1-dibromo-3,3,3-trifluoroacetone were dissolved in 400 ml of water, and the solution was heated at 80° to 90° C. for 40 minutes. The solution was cooled to 0° C., to which 75 g of the crude 2-fluoro-4-chloro-5-hydroxyphenylhydrazine hydrochloride crystals obtained above was added, and the mixture was stirred at room temperature for 70 minutes. The precipitated crystals were collected by filtration and dried under reduced pressure, which afforded 35.4 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10]O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[NH2:10][N:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[N:5][C:4]1=[NH2+:9]
Reactant: Cc1cc(C)nc(N)n1
Reactant: NO
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)n(N)c(=[NH2+])n1
Temperature: 0 °C

Procedure:
To a solution of 4,6-Dimethyl-pyrimidin-2-ylamine (25 g, 200 mmol) in 400 mL of CH2Cl2 was added dropwise a solution of hydroxylamine-2,4,6-Trimethyl-benzenesulfonate (105 g, 488 mmol) in 300 mL of CH2Cl2 at 0° C., and the mixture was stirred at 0° C. for 1 hand filtered. The solid collected was washed with CH2Cl2 (100 mL) to give 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate (40 g, yield: 62%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].[CH:12]([NH:15][CH2:16][C:17](O)=[O:18])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[C:10]1=[S:11])[CH3:2]
Reactant: CCc1ccccc1N=C=S
Reactant: CC(C)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccccc1N1C(=O)CN(C(C)C)C1=S
Yield: 26 %

Procedure:
The title compound was prepared by the procedure described in Example 18 using 16.3 g of 2-ethylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (6.8 g) as a white solid, m.p. 103°-105° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.08; H, 6.92; N, 10.62. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1.[Cl:19][C:20]1[C:21]([N:26]2[CH:30]=[C:29]([CH:31]=O)[C:28]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1.CN1CCOCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:13][CH2:14][N:15]([CH2:31][C:29]4[C:28]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:27][N:26]([C:21]5[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][N:22]=5)[CH:30]=4)[CH2:16][CH2:17]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1nn(-c2ncccc2Cl)cc1C=O
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCOC(=O)c1nn(-c2ncccc2Cl)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]hydrochloride (0.35 g, 1.1 mmol) and ethyl 1-(3-chloropyridin-2-yl)-4-formyl-pyrazole-3-carboxylate (0.3 g, 1.0 mmol) in 1,2-dichloroethane (20 mL) is added N-methyl morpholine (0.33 g, 3.2 mmol) and molecular sieves (0.10 g). The reaction mixture is stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.58 g, 2.7 mmol) is added and stirred at room temperature for 16 h. After completion, the reaction mixture is filtered through celite and partitioned between dichloromethane (15 mL) and water (15 mL). The aqueous phase is extracted with dichloromethane (3×30 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (98:2) to yield 0.4 g (67%) of ethyl 4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-3-carboxylate. MS (m/z): 543 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:35][C:34](=O)[C:32]=2[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:35]/[C:34](=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])/[C:32]=2[CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C1\Cc2ccc(OCc3ccccc3)cc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
At −78° C., Lithium bis(trimethylsilyl)amide (1.0 M in THF) (7.1 mL, 7.1 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (1.2 mL, 7.1 mmol) in THF (6 mL). It was maintained at −78° C. for 12 min. 5-(Benzyloxy)cyclobutabenzen-1(2H)-one (3.2) (0.88 g, 3.9 mmol) in THF (3 mL) was added in one portion. It was stirred at −78° C. and allowed to r.t. overnight. EtOAc (300 mL) was added and it was washed with brine and dried over Na2SO4. After removing solvent, the residue was purified by chromatography (silica gel, 1:6 EtOAc/hexane) to give 3.4 in 14% yield.