Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[Mg].II.[C:9]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])(=[O:13])/[CH:10]=[CH:11]/[CH3:12].Cl>C(OCC)C>[CH3:12][CH:11]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][C:9]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])=[O:13]
Reactant: C/C=C/C(=O)OC(C)CC
Reactant: CCCCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(C)CC(=O)OC(C)CC
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 388.1 %

Procedure:
Several drops of a solution of 4.9 g of n-butyl bromide in 126 ml of dry diethyl ether were added to a suspension of 10.53 g of magnesium and a trace amount of iodine in 80 ml of dry diethyl ether, and the mixture was stirred vigorously. The colour of the iodine disappeared upon slight heating, and the rest of the n-butyl bromide solution was then added dropwise at a rate sufficient to maintain a constant reflux of the reaction mixture. After addition of the n-butyl bromide solution the reaction mixture was heated to reflux for a further 15 minutes and was then cooled to 5° C. with an ice-water bath. Cuprous chloride (0.589 g) was divided into seven equal portions: one portion was added to the reaction mixture and then a solution of 23.9 g of sec-butyl crotonate in 120 ml of dry diethyl ether was added dropwise over 3 hours, during which time the six remaining portions of cuprous chloride were added at 30-minute intervals. After stirring the mixture at 5° C. for 15 minutes and then at room temperature for 1 hour, the reaction mixture was gradually poured into an ice-cooled mixture of 150 g of ice, 50 ml of concentrated hydrochloric acid and 60 ml of diethyl ether with vigorous stirring. The organic layer was separated from the reaction mixture obtained and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and then concentrated. The residue was purified by distillation under reduced pressure to give 27.8 g of the title compound having the following physical characteristics:
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH2:9]([O:11][P:12]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:13][CH2:14][CH3:15])=[O:16])[CH3:10]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)C(C)P(=O)(OCC)OCC

Procedure:
Ethyl 2-bromopropanoate (30.0 g.) and triethylphosphite (70.0 g.) were heated overnight at 150° C. under an air condenser. The resulting crude mixture was purified by distillation, the ethyl 2-(diethylphosphono)propanoate was collected at 66°-68° C. at 0.3-0.5 mm.Hg.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([SH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[N:2]=[C:1]([C:3]3[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=3)[S:28][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Yield: 50.4 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (1.6 g, 6.9 mmol) and 4-chlorothiosalicylic acid (2.6 g, 13.7 mmol) were dissolved in pyridine (15 ml), and the mixture was refluxed for 13 hrs. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.4 g, 51%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1
Reactant: O=c1n(-c2ccc(OC(F)(F)F)cc2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(c3ccc(OC(F)(F)F)cc3)C2=O)cc1
Reaction time: 5 h
Yield: 85.6 %

Procedure:
To a solution of 1-(4-nitrophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one (144 mg, 0.395 mmol) in 40 mL of EtOH was added 100 mg of 10% palladium on carbon. The mixture was evacuated and flushed with nitrogen three times. The Parr vessel was pressurized to 45 psi of hydrogen and shaken for 5 h. The depressurized solution was filtered through a pad of Celite® and the pad was washed with EtOH (25 mL). The ethanol was removed under reduced pressure to afford the title product (114 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=9.2 Hz, 2H), 7.33 (d, J=9.2 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.71 (d, J=9.2 Hz, 2H), 3.92 (s, 4H), 3.61 (bs, 2H); EIMS 307 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:28]C.B(Br)(Br)Br>ClCCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:28]
Reactant: COc1cc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)ccc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCCl
Product: Oc1cc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 2-{3-[3-(4-fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline (193 mg, 0.5 mmol) in 1,2-dichloro-ethane (5 mL) was added BBr3 (250 mg, 1.0 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water, extracted with DCM (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 2-fluoro-5-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (111 mg, 0.31 mmol yield 62%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([OH:26])[CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:26][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=3)[CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)c1ccc(C=NOCCOc2ccc(C(=O)O)c(O)c2)cc1
Product: CC(C)(C)c1ccc(C=NOCCOc2ccc(C(=O)O)c(OCc3ccc(C(F)(F)F)cc3)c2)cc1

Procedure:
The title compound was prepared as a white solid from 4-{2-[({[4-(tert-butyl)phenyl]methylidene}amino)oxy]-ethoxy}-2-hydroxybenzoic acid and 4-trifluromethyl benzyl bromide using a procedure similar to that of step 1 of example 6 followed by a procedure similar to that of step 3 of example 1. mp=164.1-164.8° C.; mass spectrum (+APCI, M+H) m/z 516. 1H NMR (400 MHz, DMSO-d6); δ 12.30 (s, 1H), 8.24 (s, 1H), 7.72 (m, 5H), 7.53 (d, 2H), 7.42 (d, 2H), 6.75 (d, 1H), 6.63 (dd, 1H), 5.29 (s, 2H), 4.41 (t, 2H), 4.3 (t, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C28H28F3NO5: C, 65.24; H, 5.47; N, 2.72, Found: C, 63.30; H, 5.21; N, 2.68.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]
Reactant: O=Cc1cccc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Product: O=Cc1cccc(OCc2ccc3ccccc3c2)c1
Yield: 93 %

Procedure:
2-Bromomethylnaphthalene was reacted with 3-hydroxybenzaldehyde using the procedure described in Example 1 to give 3-(naphth-2-ylmethoxy)benzaldehyde in 93% yield, m.p. 108°-110° C. (recrystallised from ethanol). The product so obtained was reacted with thiazol-2-yl-lithium using the procedure described in the 4th paragraph of the portion of Example 1 which is concerned with the preparation of starting materials except that the product was purified by column chromatography using a 1:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and diethyl ether as eluent. There was thus obtained the required starting material in 62% yield, m.p. 105°-106° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1([OH:26])[CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]2([OH:26])[CH2:25][CH2:24][CH2:23]2)[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CC1(O)CCC1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2(O)CCC2)c1

Procedure:
Sonogashira reaction of 39 with 1-ethynyl-cyclobutanol yielded tert-butyl 3-hydroxy-3-(3-(2-(1-hydroxycyclobutyl)ethynyl)phenyl)propylcarbamate as yellow oil. Yield (1.5 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.27-7.34 (m, 3H), 4.85 (bs, 1H), 4.71 (m, 1H), 3.48-3.51 (m, 2H), 3.14-3.16 (m, 1H), 2.50-2.52 (m, 2H), 2.30-2.49 (m, 3H), 1.80-1.90 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH2:19][CH2:20][C:21]#N)[CH3:18])[N:4]=1.[NH3:23]>[Ni].C(O)C>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH3:18])[CH2:19][CH:20]([NH2:23])[CH3:21])[N:4]=1
Reactant: N
Reactant: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: COc1cc2nc(N(C)CC(C)N)nc(N)c2cc1OC

Procedure:
100 gms, 0.309 moles of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride, 100 gms of Raney-Nickel and 1250 ml of solution of 6.9% ammonia in denatured spirit (denatured ethanol) were charged in an autoclave.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc(-c2ccccc2Br)n1
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2Br)n1
Yield: 54.1 %

Procedure:
6-(2-bromophenyl)-2-methylpyridine (3.5 g) was dissolved in 150 ml 1,4-dioxane. Selenium dioxide (Aldrich, Gold Label, 2.0 g) was added and the mixture was refluxed for a total of 50 hours. The solids were removed by filtration and the mixture was diluted with ether. The solution was washed several times with water, dried over magnesium sulfate, filtered and evaporated to afford 2.0 g of crude 6-(2-bromophenyl)-2-pyridinecarboxaldehyde as a yellow semi-solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C@@H:15]12[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.CCN(C(C)C)C(C)C>C(O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:16][C@H:15]4[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:19]([CH2:20][CH2:21]4)[CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2
Yield: 68.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (312 mg, 1.40 mmol), (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (312 mg, 1.47 mmol) and DIPEA (0.36 ml, 2.10 mmol) in ethanol (7.00 ml) was heated at 70° C. for 18 hours. On cooling a white precipitate formed which was collected by filtration, washed with ethanol (10 mL) and dried under vacuum to afford (1R,5S)-tert-butyl 3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (384 mg, 69%) as a white crystalline solid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8](C)=[CH:9][C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[C:29](Cl)(=[O:36])C1C=CC=CC=1>N1C=CC=CC=1>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:36][CH3:29])=[CH:9][C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: Cc1cc(O)c(C2OC(CO)CC(O)C2O)cc1Cc1cc2ccccc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(O)c(C2OC(CO)CC(O)C2O)cc1Cc1cc2ccccc2s1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of allyl α-D-glactonpyranoside (1, 5.0 g, 22.7 mmol) in 100 mL of dry pyridine at −35˜−30° C. was added benzoyl chloride dropwise with stirring. The reaction mixture was stirred at that temperature for 20 mins, then warmed to room temperature and stirred at room temperature for 48 h. The reaction was quenched by the dropwise addition of the reaction mixture to 200 ml of ice-cold saturated aqueous sodium bicarbonate with stirring. The aqueous mixture was extracted with EtOAc three times (150 ml each time). The combined extracts were washed with 1N HCl six times, brine, dried over Na2SO4, then evaporated to dryness in vacuo to give the crude product as light orange oil, which was purified by flash column chromatography on silica gel (150 g AnaLogix column, EtOAc/heptane: 0>>>5%>>>15%>>>35%) to yield compound 2 (8.55 g, 70.7%) as a white solid. 1H NMR (CDCl3) δ 8.07 (s, 1H), 8.05 (d, J=1.01 Hz, 1H), 8.01 (dd, J=3.03, 1.52 Hz, 2H), 7.99 (dd, J=3.03, 1.52 Hz, 2H), 7.59 (m, 1H), 7.52 (m, 2H), 7.46 (t, J=7.58 Hz, 2H), 7.35-7.42 (4H), 5.86 (ddd, J=16.67, 11.12, 5.56 Hz, 1H), 5.79 (dd, J=11.12, 0.03 Hz, 1H), 5.70 (dd, J=10.61, 3.54 Hz, 1H), 5.35 (d, J=3.54 Hz, 1H), 5.27 (dq, J=17.18, 1.52 Hz, 1H), 5.12 (dq, J=10.61, 1.52 Hz, 1H), 4.68 (dd, J=11.62, 6.57 Hz, 1H), 4.55 (dd, J=11.12, 6.57 Hz, 1H), 4.42 (m, 2H), 4.25 (m, 1H), 4.10 (m, 1H), 2.47 (d, J=4.04 Hz, 1H). MS (ES) 554.8 (M+Na+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[C:5]([CH3:32])[CH:4]=1)#[N:2].IC.[C:35](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:35])=[N:10]2)=[C:5]([CH3:32])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyano-2-methylphenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate Example 21; 100 mg, 0.22 mmol), 1-iodomethane (34.0 mg, 0.24 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][S:8][C@H:9]([CH:10]=[O:11])[C@H:4]2[O:3]1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][S:8][C@H:9]([CH2:10][O:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](CS[C@@H]2C=O)O1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)O[C@H]2[C@H](CS[C@@H]2COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a solution of 111 (2.1 g, 11.1 mmol) in pyridine (20 mL) was added benzoyl chloride (1.9 g, 13.4 mmol) at 0° C. and the reaction mixture was stirred for 6 h at room temperature before being quenched with methanol. The reaction mixture was evaporated under reduced pressure. The residue was then taken up in diethyl ether (50 mL), and the pyridinium salt was filtered and washed with diethyl ether. The combined organic layer was concentrated and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to afford the benzoate 112 (3.2 g, 99%) as a colorless oil: 1H NMR (CDCl3) δ 1.26 (s, 3H, CH3), 1.47 (s, 3H, CH3), 2.87 (dd, 1H, J=13.2, 1.5 Hz, 6-CHH), 3.11 (dd, 1H, J=13.2, 4.9 Hz, 6–CHH), 3.57 (m, 1H, 4-H), 4.25 (dd, 1H, J=11.5, 8.0 Hz, BzOCHH), 4.35 (dd, 1H, J=11.4, 5.8 Hz, BzOCHH), 4.72 (dd, 1H, J=5.6, 1.2 Hz, 6a-H), 4.91 (td, 1H, J=4.4, 1.2 Hz, 3a-H), 7.35–7.99 (m, 5H, Ph); FAB-MS m/z 294 (M+); Anal. Calcd for C15H18O4S: C, 61.20; H, 6.16; S, 10.89. Found: C, 60.99; H, 6.42; S, 10.77.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[CH:20]=[C:21]([CH:25]2[C:29]3[C:30]([CH3:44])=[C:31]([NH:36][C:37](=[O:43])[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:32]([CH3:35])=[C:33]([CH3:34])[C:28]=3[O:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)=O.O>CN(C=O)C>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:37]([NH:36][C:31]1[C:32]([CH3:35])=[C:33]([CH3:34])[C:28]2[O:27][CH2:26][CH:25]([C:21]3[CH:20]=[C:19](/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]=[CH:23][CH:22]=3)[C:29]=2[C:30]=1[CH3:44])=[O:43]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C=O)c1)CO2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of sodium hydride (a 60% dispersion in liquid paraffin, 79 mg, 1.98 mmol) in DMF (10 mL) was added dropwise at 0° C. under an argon atmosphere ethyl diethylphosphonoacetate (444 mg, 1.98 mmol) and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise at 0° C. a solution of N-(3-(3-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (684 mg, 1.80 mmol) obtained in Example 173 in DMF (5 mL) and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, was added to water and the product was extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 750 mg (yield: 93%) of the title compound. Melting point: 199-200° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:18]>C(O)C>[NH2:18][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Temperature: 120 °C
Reaction time: 96 h
Yield: 22 %

Procedure:
Under a N2 atmosphere, a mixture of 6-chloro-N-(thiazol-2-yl)pyridine-3-sulfonamide (0.7 g, 2.54 mmol), ammonium hydroxide (7.5 mL) and ethanol (7.5 mL), was stirred at 120° C. in a sealed tube for 4 days. The reaction was cooled to RT. After evaporating the solvents under reduced pressure, purification via silica gel chromatography using 5%-10% methanol in CH2Cl2 gave 6-amino-N-(thiazol-2-yl)pyridine-3-sulfonamide as a orange solid (0.14 g, 22%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=257.2; tR=0.2 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@H:13]([C:15]([NH:17][C@H:18]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:16])[CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH:18]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:16])[CH3:14])=[O:11]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: C[C@H](N)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)Nc1c(F)cccc1F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure (5-A1) using 2,6-difluorophenyl isocyanate and (S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 491 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH:6]2[CH:7]([CH3:8])[CH:5]2[C:3]1=O.COCCO[AlH2-]O[CH2:18][CH2:19]OC.[Na+].[OH-].[Na+].[ClH:25]>C1C=CC=CC=1>[ClH:25].[CH3:1][N:2]1[CH2:9][CH:6]2[C:5]([C:19]3[CH:18]=[CH:7][CH:6]=[CH:5][CH:3]=3)([CH:7]2[CH3:8])[CH2:3]1
Reactant: COCCO[AlH2-]OCCOC
Reactant: CC1C2C(=O)N(C)C(=O)C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC1C2CN(C)CC12c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of N,3-dimethylcyclopropane-1,2-dicarboximide (U.S. Pat. No. 3,166,571, Ex. 2) in benzene is added Vitride® for several minutes. This solution is stirred at ambient temperature for several hours, refluxed for one hour, and then cooled and combined with sodium hydroxide and worked-up and converted to the hydrochloride to give the title product.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH3:13])([O-:12])=[O:11].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:22]=[N:23]/[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:13][N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(Cl)c1Cl
Reactant: C[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
263 μl (1.51 mmol) of N,N-diisopropylethylamine were added to 10.1 ml (186 mmol) of nitromethane, and the yellow solution was stirred at RT for 1 h. 1.38 g (5.03 mmol) of the compound of Example 22A were then added, and the mixture was stirred at RT overnight. All volatile components were removed on a rotary evaporator. The residue was purified by preparative HPLC [Method 12]. This gave 865 mg (51% of theory) of the title compound.