Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[C:7]([C:11]1[O:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:17]=2[N+:25]([O-:27])=[O:26])[C:13](=[O:28])[C:12]=1[CH2:29][Cl:30])([CH3:10])([CH3:9])[CH3:8].C(OC(Cl)=O)C.[CH2:37]([NH2:53])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>O.C(N(CC)CC)C>[C:7]([C:11]1[O:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:23])[NH:53][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:18][C:17]=2[N+:25]([O-:27])=[O:26])[C:13](=[O:28])[C:12]=1[CH2:29][Cl:30])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)c1on(-c2ccc(C(=O)O)cc2[N+](=O)[O-])c(=O)c1CCl
Reactant: CCCCCCCCCCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCNC(=O)c1ccc(-n2oc(C(C)(C)C)c(CCl)c2=O)c([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 0.83 h

Procedure:
Ethyl acetate (480 ml) was mixed with 81.6 grams of 5-t-butyl-4-chloromethyl-2-(4-carboxy-2-nitrophenyl)-4-iso-oxazolin-3-one and the mixture was cooled to -15° C. Triethylamine (32.6 ml) was added dropwise to this suspension and then 22.0 ml of ethylchlorocarbonate was added dropwise while maintaining the temperature below -10° C. Hexadecylamine (49 grams) was added after reacting for a further period of 50 minutes. After reacting the mixture at -10° C. for a period of 10 minutes the temperature was gradually raised to room temperature and the mixture was left to stand overnight. Next 400 ml of water was added, the mixture was separated and the organic layer was recovered and concentrated to dryness. The residue was recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[N:32]=[C:31]([Cl:33])[C:30]([F:34])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]>C1COCC1>[Cl:33][C:31]1[C:30]([F:34])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[N:32]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)c(F)cc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine (19.2 g, 105 mmol) in anhydrous THF (50 mL) was added a solution of LHMDS (160 mL, 1 M in hexanes, 160 mmol) dropwise over 45 minutes under a nitrogen atmosphere. After 2 hours at −78° C., a solution of 2,6-dichloro-5-fluoro-nicotinic acid (10.5 g, 50 mmol) in anhydrous THF (30 mL) was added. The mixture was stirred at −78° C. for 1 hour then allowed to warm to ambient temperature. After 18 hours stirring at ambient temperature the reaction was quenched with water and adjusted to pH 2 by the addition of concentrated HCl. The solution was extracted with ethyl acetate and the organic layer was isolated, washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated with methanol and filtered to afford the title compound as a yellow solid (8.7 g, 49%). LCMS (method B): RT=4.92 min, [M+H]+=357.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH2:12][NH:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[C:23]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C.CC(=O)OCC>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH:10]1[CH2:13][CH2:12][N:11]1[S:29]([C:24]1[C:23]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:31])=[O:30])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN1S(=O)(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
To a cold (5° C.) solution of 2-(N-Boc-aminomethyl) azetidine (200 mg), DIEA (0.375 mL) in dry DMF (2 mL), was added portionwise biphenyl-2-sulfonyl chloride (272 mg). The reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EA, washed with water. The organic extract was dried (MgSO4), filtered and concentrated to yield the crude product as light brown oil (295 mg, 68%) which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:31]([C:33]([CH3:36])([CH3:35])[CH3:34])#[C-:32]>CO>[C:33]([NH:31][C:32]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][C:9]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])([CH3:36])([CH3:35])[CH3:34]
Reactant: Nc1ccc(F)cn1
Reactant: N#Cc1cccc(C=O)c1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)Nc1c(-c2cccc(C#N)c2)nc2ccc(F)cn12
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
5-fluoropyridin-2-amine (200 mg, 1.78 mmol, Eq: 1.00), 3-formylbenzonitrile (246 mg, 1.87 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (102 mg, 535 μmol, Eq: 0.3) were dissolved in MeOH (2.00 mL) and the intensive yellow solution was stirred for 20 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (148 mg, 203 μL, 1.78 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 1 h whereupon a white precipitate was formed. The precipitate was filtered off, washed with MeOH (4 mL) and dried under vacuum to give the product as an off-white solid (323 mg, 58.7%). MS: 308.0 [M]+; 1H-NMR (CDCl3): δ 8.35 (s, 1H), 8.26 (d, 1H), 8.14 (m, 1H), 7.63 (d, 1H), 7.60-7.52 (m, 2H), 7.13 (ddd, 1H), 3.01 (s, 1H), 1.10 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]#N)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[Na+].Cl.C[OH:23]>>[C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:23])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: N#CCc1c(-c2ccccc2)nn2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetonitrile (0.23 g), 85% sodium hydroxide (0.33 g) and 80% aqueous methanol was refluxed for 15 hours. The reaction mixture was acidified with 5% hydrochloric acid (pH≈1) and the precipitates were collected by filtration to give 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetic acid (0.23 g).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4]/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:25][C@@H:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27](O)=[O:28]>C1(C)C=CC=CC=1>[N:17]1([CH2:16][CH2:15][NH:14][C:8]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]2[N:5]([CH2:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:27](=[O:28])[C@H:26]([CH2:30][C:31]([OH:33])=[O:32])[S:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)C[C@H](S)C(=O)O
Reactant: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cccc(F)c1NCCN1CCCCC1

Procedure:
2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-(piperidin-1-yl)ethyl)benzenamine (457 mg, 1.370 mmol) and (S)-2-mercaptosuccinic acid (224 mg, 1.492 mmol) were stirred in toluene (14 mL) at 80° C. for 24 hours. The solvent was removed on a rotary evaporator under high vacuum at 35° C. Crude 2-((5S)-2-(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid was obtained as a brown foam and carried on to the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH3:35])=[CH:22][CH:21]=2)[CH:19]=1)=[O:14])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].Cl>O1CCOCC1.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][N:4]([C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH3:35])=[CH:22][CH:21]=2)[CH:19]=1)=[O:14])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO)CC(=O)OC(C)(C)C)cn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO)CC(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of tert-butyl N-(2-hydroxyethyl)-N-{[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]carbonyl}glycinate prepared in Example 67-(3) (0.218 g) in 1,4-dioxane (4.0 ml), a solution of hydrochloric acid in ethyl acetate (4 M, 4.0 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by octadecylsilyl (ODS) column chromatography (eluting solvent: acetonitrile:water=95:5) to give the titled compound (0.075 g) as a colorless amorphous substance.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](O)=[O:38])=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]1[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1)=[O:81]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH:22]=2)[C@@H:13]1[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:81])=[O:38])=[CH:40][CH:41]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)NCC(=O)N[C@H](CC2CCCCC2)C(=O)O)cc1)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.08 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (25.1 mg, 0.040 mmol) was dissolved in DMF (1 ml, dry). N-methylmorpholine (13 μl, 121 mmol) was added and the reaction mixture was stirred at 30° C. for five minutes. TBTU (20.1 mg, 0.063 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (12.5 mg, 0.055 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was purified with preparative HPLC on a C8 column. A gradient from 10 to 100% MeCN in 0.1M NH4OAc buffer was used as eluent. Most of the MeCN was removed under reduced pressure. The residue was diluted with water and lyophilised to give the title compound, M/z: 921 (M−1).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:40]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(N[C@H](Cc1ccccc1)CN(Cc1ccccc1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)OCc1cncs1
Yield: 18.4 %

Procedure:
The product from Example 31D (80 mg, 0.141 mmol), benzaldehyde (17 μl, 0.170 mmol), acetic acid (10 μl, 0.166 mmol), and sodium triacetoxyborohydride (48 mg, 0.226 mmol) were processed as described in Example 27 to provide the title compound (17 mg, 18%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.78 (s, 2H), 7.32-7.08 (m, 15H), 5.12 (br s, 2H), 4.84 (brs, 2H), 4.12 (s, 2H), 3.13 (dd, 2H), 3.05-2.87 (m, 6H), 2.80-2.70 (m, 2H); MS (ESI+) m/z 656 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]([F:24])([F:23])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)[OH:10].[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([Cl:33])[N:27]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:33][C:28]1[CH:29]=[C:30]([O:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[C:8]([F:7])([F:23])[F:24])[N:31]=[C:26]([NH2:25])[N:27]=1
Reactant: OC(c1ccccc1-c1cncnc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc(Cl)cc(OC(c2ccccc2-c2cncnc2)C(F)(F)F)n1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
Cs2CO3 (325 mg, 1.0 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethanol (72 mg, 0.28 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 min, 2-amino-4,6-dichloro-pyrimidine (36.7 mg, 0.22 mmol) was added and then the reaction mixture was heated at 110° C. until the reaction was completed. After cooling to room temperature, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 76 mg of crude 4-chloro-6-[2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (yield: 92%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][SH:4](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(C)C=C(C)C=C(C)C=1S([NH:31]O)(=O)=O>ClCCl>[NH2:31][N:7]1[C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[SH:4](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][C:2]1=[NH:1]
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: NC1=Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1
Solvent: ClCCl
Product: N=C1N[SH](=O)(c2ccccc2)c2cc(Cl)ccc2N1N
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To 18.2 g of 3-amino-7-chloro-1-phenyl-1,2,4-benzothiadiazine-1-oxide is slowly added with stirring a solution of 16.1 g of mesitylene sulfonylhydroxylamine in 90 ml dichloromethane at 0° C. Stirring is continued for one hour at room temperature. Thereafter the precipitate is sucked off and washed with diethylether carefully. To the dry precipitate (30.4 g), suspended in 200 ml dioxane, 60 ml of 20% aqueous sodium hydroxide is added with stirring at 0° C. Stirring is continued for three hours at room temperature. Thereafter the precipitate is sucked off and the filtrate is poured into ice water. The precipitate is sucked off and crystallized from ethanol. A 16.0 g of colorless 4-amino-7-chloro-3,4-dihydro-3-imino-1-phenyl-1,2,4-benzothiadiazine-1-oxide, m. pt. 168° C., are obtained. A 6.5 g thereof in 25 ml ethyl oxalate chloride is heated for five hours to 80° C. The excess of acid chloride is distilled and the residue partitioned in dichloromethane/aqueous sodium hydrogencarbonate. The organic solvent is distilled in vacuo and the residue crystallized from ethanol, recrystallized from toluene and again from ethanol. A 3.5 g colorless crystals are obtained, m. pt. 239° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Br[C:13]1C=C(F)C(F)=C(F)C=1.[Mg].O=[C:24]1[N:29](C(O)=O)[C@@H:28]([C:33]([OH:35])=[O:34])[CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH3:13][O:35][C:33]([C@H:28]1[CH2:27][CH2:26][CH2:25][C@@H:24]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[NH:29]1)=[O:34]
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Reactant: O=C(O)[C@H]1CCCC(=O)N1C(=O)O
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere and at −78° C., 3,4,5-trifluorophenyl magnesium bromide (prepared from 1-bromo-3,4,5-trifluorobenzene (11.7 g) and magnesium (1.48 g) according to the method described in Org. Synth., 2001, 79, 176) was added to a THF (140 mL) solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tertiery butyl ester (13.0 g) over 30 minutes. The reaction solution was stirred for 2 hours from −78° C. to −10° C. Afterwards, at −10° C., the resultant reaction was quenched with saturated ammonium chloride aqueous solution. Water was added to the reaction solution, and extraction with ethyl acetate was conducted. After drying the resulting extraction solution with magnesium sulfate, concentration under a vacuum was conducted. A 4 N hydrochloric acid ethyl acetate solution (150 mL) was added at room temperature to an ethyl acetate (150 mL) solution of the residue. The resultant reaction solution was stirred for 9 hours at room temperature. The reaction solution was concentrated under a vacuum, and after making the residue basic by adding saturated sodium bicarbonate solution, chloroform was added, and stirring was continued for 2 hours at room temperature. The organic layer was partitioned, and after drying with magnesium sulfate, the resultant was concentrated under a vacuum. 10% palladium on carbon (700 mg) was added to a methanol (200 mL) solution of the residue, and the resultant reaction solution was stirred for 9 hours under a hydrogen atmosphere and at room temperature. The reaction solution was filtered over celite, and the filtrate was concentrated under a vacuum. By purifying the residue by silica gel column chromatography (eluting solvent:heptane-ethyl acetate system), 5.47 g of the title compound was obtained. The physical property values are as follows.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: OC(CCl)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
2-Chloro-3′-chloroacetophenone (94.5 mg; 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamrethylcyclopentadienyl)iridium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diaminocyclohexane (3.5 mg, 0.0005 mmol, s/c=100) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (+)-2-chloro-1-(3′-chlorophenyl)ethanol (88.5 mg; yield: 92.7%; optical purity: 91.0%).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:30]=[CH:29][C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CCOC(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:29]=[CH:30][C:14]([S:11]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:3]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(Cl)c3ccccc32)cc1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(N3CCCCC3)c3ccccc32)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
Dissolve 4-(3-chloro-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (91 mg, 0.20 mmol) in piperidine (1.0 mL) and stir at 90° C. overnight. Dilute the solution with EtOAc (30 mL) and wash with 1N HCl (15 mL) and satd NaHCO3 (15 mL). Dry, filter and concentrate the organic solution and purify the residue by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes, to give the title compound as a light yellow foam (7 mg, 7%). MS (ES) 493.0 (M+1)+, 491.2 (M−1)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][CH2:38][OH:39])[N:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:40]([O:42][C:43](=[O:59])[CH2:44][CH:45]([N:49]1[C:57]2[C:52](=[CH:53][C:54](O)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1)[CH2:46][CH2:47][CH3:48])[CH3:41].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:20]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][CH2:38][O:39][C:54]3[CH:53]=[C:52]4[C:57](=[CH:56][CH:55]=3)[N:49]([CH:45]([CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:59])[CH2:46][CH2:47][CH3:48])[CH:50]=[CH:51]4)[N:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCO)nc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
Triphenylphosphine (0.20 g, 0.77 mmol) was added to a solution of 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.16 g, 0.58 mmol) and 3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester (0.10 g, 0.38 mmol) in THF (4 mL) at 0° C. Diisopropylazodicarboxylate (0.15 g, 0.77 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The solution was then concentrated. The residue was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title compound (13% yield). 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.09 (m, 2H), 6.96 (d, 1H, J=7.6 Hz), 6.86 (m, 1H), 6.41 (d, 1H, J=3.2 Hz), 4.78 (m, 1H), 4.39 (t, 2H, J=6.9 Hz), 3.98 (q, 2H), J=7.1 Hz), 3.75 (m, 2H), 3.21 (t, 2H, J=6.9 Hz), 2.86 (m, 2H), 2.77 (m, 2H), 1.85 (m, 4H), 1.50 (s, 9H), 1.20 (m, 2H), 1.06 (t, 3H, J=7.1 Hz), 0.85 (t, 3H, J=7.4 Hz).
Reaction SMILES: C=O.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C1(B(O)O)C=CC=CC=1.[C:23](O)(=[O:26])CC.OO>C1C=CC=CC=1.C1COCC1.O>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:10][C:9]=1[CH2:23][OH:26]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)O
Agent: C=O
Agent: OB(O)c1ccccc1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: OCc1cc(C(F)(F)F)ccc1O
Reaction time: 1 h
Yield: 70.6 %

Procedure:
Paraformaldehyde (3.4 g, 0.114 mol) was added in 0.5 g portions over a six hour period to a refluxing mixture of 4-trifluoromethyl phenol (2.3 g, 0.0142 mol), phenyl boronic acid (2.1 g, 0.017 mol) and proprionic acid (530 μL, 7 mmol) in benzene with the azeotropic removal of water (Dean-Stark trap). When the addition was complete, the reaction was heated for an additional hour, then cooled with an ice bath, diluted with THF (30 mL) and treated with 5 mL of 30% hydrogen peroxide solution. After stirring for one hour, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with NaHSO3 solution (1×50 mL), brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 950 mg (35%) of the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H, J=9.1 Hz); 7.3 (s, 1H); 6.95 (d, 1H, J=9.1 Hz); 4.89 (s, 2H);