Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][C:37]2[CH:45]=[CH:44][C:43]([O:46][C:47]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:51][CH:50]=3)=[O:48])=[CH:42][C:38]=2[C:39]([OH:41])=[O:40])=[O:35])=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[C:67]([O:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]([O:87][C:88]2[CH:93]=[CH:92][C:91]([CH2:94]O)=[CH:90][CH:89]=2)=[O:86])=[CH:81][CH:80]=1)(=[O:70])[CH:68]=[CH2:69].O>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([O:36][C:37]2[CH:45]=[CH:44][C:43]([O:46][C:47]([C:49]3[CH:50]=[CH:51][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:53][CH:54]=3)=[O:48])=[CH:42][C:38]=2[C:39]([O:41][CH2:94][C:91]2[CH:92]=[CH:93][C:88]([O:87][C:85]([C:82]3[CH:83]=[CH:84][C:79]([O:78][CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][O:71][C:67](=[O:70])[CH:68]=[CH2:69])=[CH:80][CH:81]=3)=[O:86])=[CH:89][CH:90]=2)=[O:40])=[O:35])=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(CO)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(COC(=O)c3cc(OC(=O)c4ccc(OCCCCCCOC(=O)C=C)cc4)ccc3OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
0.2 g of N,N'-dicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 0.6 g of 2,5-bis(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)-benzoic acid, 0.4 g [4-(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)phenyl]methanol and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from acetone of the fractions which are pure according to thin-layer chromatography gives 0.4 g of [4-(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)-phenyl]-methyl 2,5-bis(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)-benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:26][C@@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][C@H:27]3[CH3:26])=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[C@@H]1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H]1COCCN1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (63 mg, 0.152 mmol), (R)-3-methyl-morpholine (100 mg, 1.0 mmol), DIEA (0.132 mL, 0.76 mmol) and HATU (86 mg, 0.23 mmol) in 1.5 mL of DMF was stirred at room temperature for 4 hours. The mixture was directly applied for preparative HPLC (20-80% acetonitrile in water) to afford the title compound as a white solid: 1H NMR: (CDCl3, ppm) δ 8.24 (d, 1H), 8.11 (m, 1H), 8.02 (m, 1H), 7.93 (m, 1H), 7.63 (d, 1H), 4.60 (m, 1H), 4.29 (m, 1H), 3.77 (m, 2H), 3.59 (m, 1H), 3.38 (m, 2H), 1.28 (m, 3H); MS: (M+H)/z=498.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:12]([CH3:13])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cccc(Cl)c2c(=O)o1
Temperature: 120 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
2-amino-6-chlorobenzoic acid (25 g) dissolved in acetic anhydride (100 ml) was stirred at 120° C. for 2 hours. The mixture was cooled to room temperature and filtered off. The precipitate was washed with water and Na2CO3 (10%) and dissolved in CH2Cl2. The solution was dried with Na2SO4, filtered off and evaporated. The residue was crystallized twice from benzene, yielding 13 g (46%) of 5-chloro-2-methyl-4H-3,1-benzoxazin-4-one; mp. 148.7° C. (interm. 14).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH3:25][O:26][CH2:27]Cl>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:25][O:26][CH3:27])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a mixture of 2-benzyloxy-5-hydroxybenzaldehyde (16.68 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 3.07 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Chloromethyl methyl ether (11.8 g) was dropwise added to the reaction mixture. The reaction mixture was further stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-methoxymethoxybenzaldehyde as a colorless oil (10.32 g, 52%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[O:28][S:37]([CH3:36])(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](O)C2=O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](OS(C)(=O)=O)C2=O)CC1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
tert-Butyl 4-((3R,4S)-4-(benzyloxy)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (525 mg, 1.34 mmol) was dissolved in THF (10 mL) and triethylamine (375 μL, 2.69 mmol) and methanesulfonyl chloride (126 μL, 1.61 mmol) were added to the reaction and stirred for 1 hour. The reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, dried over Na2SO4, filtered and concentrated to afford tert-butyl 4-((3R,4S)-4-(benzyloxy)-3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (623 mg, 1.33 mmol, 98.9% yield) as a white solid.
Reaction SMILES: CS(O[CH:6]([C:16]1[C:21]([F:22])=[C:20]([Cl:23])[CH:19]=[C:18]([C:24](=[O:26])[CH3:25])[C:17]=1[O:27][CH2:28][CH3:29])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.[Cl-].[Na+].O>[N:30]([CH:6]([C:16]1[C:17]([O:27][CH2:28][CH3:29])=[C:18]([C:24](=[O:26])[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[F:22])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-]
Temperature: 50 °C
Yield: 100 %

Procedure:
1-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl methanesulfonate (0.83 g, 1.77 mmol) (from Step 4) was stirred in dimethyl sulfoxide (10 mL) and sodium azide (0.12 g, 1.8 mmol) was added. The mixture was heated to 50° C. for 1 hour and cooled to rt. The mixture was poured into brine and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound 736 mg, 100%. LCMS calculated for C18H27ClFN3O3SiNa (M+Na)+: m/z=438.1; found: 438.1.
Reaction SMILES: [C:1]([N:4]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc(N)cc1

Procedure:
0.7 g (2.1 mmol) of 4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-nitrobenzene are dissolved in 20 ml of methanol and after the addition of 100 mg of 10% palladium on activated charcoal hydrogenated with hydrogen for 3 hours. Then the catalyst is filtered off and evaporated down.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
4-(4-Bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.23 mmol) was dissolved in a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and then dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and then water. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to yield the product as a white solid (329 mg, 88%). 1H NMR (CDCl3) δ 1.77 (s, 1H), 2.96 (m, 4H), 3.01 (m, 4H), 7.64 (dt, 2H, J=2.1, 8.7 Hz), 7.69 (dt, 2H, J=2.1, 8.7 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.[Br:30]C1C=CC(C2N=C3C=CC=CN3C=2CN)=CC=1>>[Br:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: NCc1c(-c2ccc(Br)cc2)nc2ccccn12
Product: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Br)cc3)nc3ccccn23)C1

Procedure:
The title compound was prepared according to the experimental for compound 237 from (2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)methanamine. m/e+=454 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.51 (d, 1H, D, J=5.8 Hz), 7.63 (m, 5H), 7.26 (m, 1H), 6.85 (t, 1H, D, J=6.6 Hz), 5.06 (s, 2H), 4.88 (m, 1H), 4.67 (s, 1H), 3.55 (s, 1H), 2.99 (m, 2H), 2.42 (m, 2H), 2.16 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:11])[CH2:4][N:5]1[CH:9]=[C:8](I)[CH:7]=[N:6]1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.[F-].[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.O1CCOCC1.O>[NH2:36][C:22]1[N:23]=[CH:24][C:25]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][C:3]([OH:2])=[O:11])[CH:9]=2)=[CH:26][C:21]=1[C:13]1[S:12][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: COC(=O)Cn1cc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn(CC(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 85 °C

Procedure:
A mixture of (4-iodopyrazol-1-yl)-acetic acid methyl ester (124 mg, 0.467 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (150.0 mg, 0.4246 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), potassium fluoride (74.0 mg, 1.27 mmol) and 4:1 dioxane:water (4:1, 1,4-dioxane:H2O, 6 mL) was heated in the microwave reactor at 85° C. for 30 min. The solution was concentrated in vacuo and dry-loaded onto silica gel for column chromatography. The material was eluted with 2% MeOH/DCM. The fractions containing the product were concentrated in vacuo. The material was redissolved in 1,4-dioxane (5 mL), and 4M HCl in 1,4-dioxane (1 mL) was added. The solution was heated to 50° C. in a sealed tube for 3 h. The solvent was removed in the corrosive pump to afford the title compound as an orange solid. MS (ES+): m/z=352.08 (100) [MH+]. HPLC: tR=2.78 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[OH:5][CH2:4][C:3]1[C:2]([CH3:1])=[N:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cccnc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ncccc1CO
Reaction time: 0.08 h
Yield: 167.8 %

Procedure:
Prepared according to a slightly modified procedure of I. M. Bell et al., J. Med. Chem. 41, 2146–2163 (1998). To a stirred solution of ethyl 2-methylnicotinate (2.0 g, 12.1 mmol) in tetrahydrofuran (40 mL) cooled to 0° C. was slowly added a 1 M solution of diisobutyl aluminum hydride in tetrahydrofuran (30 mL, 30 mmol). After 5 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate and saturated aqueous sodium potassium tartrate. The aqueous phase was repeatedly extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.5 g of the crude title compound as a yellow oil. The crude material was used as such in the next step.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([N:11]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]([CH3:25])([CH3:24])[CH2:12]2)=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C[Si](I)(C)C>C(Cl)(Cl)(Cl)Cl.O>[OH:2][C:3]1[C:8]([C:9]([N:11]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]([CH3:25])([CH3:24])[CH2:12]2)=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CN(C(=O)c2cccnc2O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 50 °C
Yield: 80.8 %

Procedure:
In 6 ml of carbon tetrachloride was dissolved 0.4 g of 3,4-dihydro-4-[(2-methoxypyridin-3-yl)carbonyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine followed by dropwise addition of 0.26 g of trimethylsilyl iodide. The mixture was heated at 50° C. for 2 hours and, then, cooled. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and methanol was added to the concentrate for crystallization., Recrystallization from ethyl acetate gave 0.31 g of 3,4-dihydro-4-[(2-hydroxypyridin-3-yl)carbonyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([OH:13])(=[O:12])[CH:10]=[O:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:8])[CH:10]([OH:11])[C:9]([OH:13])=[O:12]
Reactant: Oc1ccccc1Cl
Reactant: O=CC(=O)O
Product: O=C(O)C(O)c1ccc(O)c(Cl)c1

Procedure:
o-chlorophenol is reacted with glyoxylic acid to form 3-chloro-4-hydroxymandelic acid,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[O:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH:34]1([Mg]Br)[CH2:36][CH2:35]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([CH:34]3[CH2:36][CH2:35]3)[OH:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O)c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
103 mg (0.21 mmol) of 2-[3-(4-chlorophenyl)-4-(2-oxoethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 401 are dissolved in 1 ml of THF and treated at −78° C. with 1.1 ml (0.54 mmol) of cyclopropylmagnesium bromide (0.5 M solution in THF). This is stirred for 3 hrs at RT and then for a further 2 hrs at 50° C. For the workup, it is treated with saturated ammonium chloride solution and extracted twice with 10 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 12 mg (11% of theory) of the target compound are thus obtained.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:11][CH:7]([CH2:8][NH:9][CH2:10]1)[CH2:6][S:5][CH2:4]2.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>O.C(Cl)Cl>[C:12]([N:9]1[CH2:8][CH:7]2[CH2:11][CH:3]([CH2:4][S:5][CH2:6]2)[CH2:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1NCC2CSCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)N1CC2CSCC(C2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A 10-mL, two-necked, round-bottomed flask was equipped with a magnetic stirrer, an ice bath, a standard condenser with a N2 inlet, and a glass stopper. To a chilled (5° C.) solution of NaOH pellets (0.1 g, 2.38 mmol) in H2O (1.7 mL) was added a solution of the amine (28, 0.17 g, 1.19 mmol) in CH2Cl2 (1 mL). This was followed by the dropwise addition of a solution of benzoyl chloride (0.2 g, 1.43 mmol) over ~5 min. After stirring for 30 min at 0°-5° C., 30 min at RT, and then 15 min over a steam bath, the mixture was diluted with H2O (15 mL), and the mixture was extracted (CH2Cl2, 3×15 mL). Combining the extracts, drying (Na2SO4, overnight), filtering, and concentrating the solution gave a viscous yellow oil. Chromatography of the oil on alumina (38 g, 2.4 cm×17 cm) employed ethyl acetate as eluant and afforded amide (29) (Rf =0.47) as white crystals (157 mg, 53.3%); mp 95°-96° C. IR (KBr) cm-1 3065, 3045 (Ar C--H), 3000, 2985, 2940, 2910, 2855, 2835 (C--H), 1635 (C=O), 745, 720 (C--H out of plane, mono); 1H NMR (DCCl3) δ1.78-1.93 [m, 3H, H(9) and H(1)], 2.15 [bs, 1H, H(5)], 2.39 [d, 1H, H(4)ax, J=13.9 Hz], 2.77 [d, 1H, H(6)ax, J=12.3 Hz], 3.12-3.21 [m, 3H, H(4)eq and H(6)eq ], 3.41 [d, 1H, H(2)ax, J=12.8 Hz], 3.89 [d, 1H, H(2)eq, J=13.4 Hz), 4.98 [d, 1H, H(8)eq, J=13.1 Hz], 7.38-7.44 [m, 5H, Ar--H]; 13C NMR (DCCl3) ppm 26.53 [C(1)], 26.87 [C(5)], 31.73 [C(2)], 31.78 [C(9)], 32.34 [C(4)], 46.07 [C(8)], 52.12 [C(6)], 126.46, 128.41, 128.83, 137.35 (Ar--C), 170.38 [C=O]. Anal. Calcd. for C14H17NOS: C, 67.98; H, 6.93. Found: C, 68.01; H, 7.07.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([Cl:23])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cc(I)cc1Cl
Solvent: Cc1ccccc1
Product: Fc1c(N=C(Cl)c2c(Cl)cc(I)cc2Cl)ccnc1Cl
Yield: 99 %

Procedure:
A solution of 2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-iodobenzamide (2.83 g, 6.4 mmol) in thionyl chloride (23 mL) was heated to 90° C. for 56 hours then diluted with toluene and concentrated under reduced pressure to give the desired compound (2.94 g, 99% yield). 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=5.1 Hz, 1H), 7.84-7.76 (m, 2H), 6.95 (t, J=5.1 Hz, 1H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 115 °C
Yield: 40 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride was dissolved in dimethyl sulfoxide (1.0 mL). 2-Chloro-5-(trifluoromethyl)pyridine (28.0 mg, 0.154 mmol, 1.5 equivalents) and sodium carbonate (65.5 mg, 0.618 mmol, 6.0 equivalents) were added, and the resulting suspension was heated to 115° C. for 14 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine, and then dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified via silica chromatography on 2 sequentially linked 4 g silica cartridges, eluting with 25:75 to 0:100 heptanes:ethyl acetate to give the titled compound (16 mg, 40% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.42 (s, 1H), 7.96 (dd, J=14.0, 1.2 Hz, 2H), 7.67 (dd, J=9.0, 2.4 Hz, 1H), 6.66 (d, J=9.0 Hz, 1H), 5.48 (t, J=4.0 Hz, 1H), 4.81 (d, J=14.6 Hz, 1H), 4.37-4.32 (m, 1H), 4.19-4.10 (m, 1H), 4.04 (dd, J=13.9, 2.2 Hz, 1H), 3.73 (dd, J=13.8, 4.1 Hz, 1H), 3.54-3.36 (m, 1H), 3.04 (dd, J=14.5, 9.4 Hz, 1H), 2.75 (dd, J=6.6, 3.6 Hz, 2H), 2.55 (dd, J=13.8, 5.1 Hz, 1H), 2.05-1.95 (m, 2H), 0.98-0.91 (m, 4H); 1H NMR (400 MHz, pyridine-d5) δ ppm 8.63 (s, 1H), 8.16 (d, J=1.1 Hz, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 5.52 (t, J=4.0 Hz, 1H), 4.82 (d, J=14.5 Hz, 1H), 4.53-4.24 (m, 3H), 3.92 (dd, J=13.6, 4.1 Hz, 1H), 3.40 (ddd, J=14.7, 10.2, 1.9 Hz, 1H), 3.07 (dd, J=14.5, 9.4 Hz, 1H), 2.89-2.72 (m, 2H), 2.65-2.47 (m, 1H), 2.11-1.91 (m, 2H), 1.10-0.97 (m, 2H), 0.97-0.81 (m, 2H); MS (ESI+) m/z 434.1 (M+H)+; [α]D24.8=−3.2 (c=0.41, CH3OH).