Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:13]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[CH:16][CH2:17]3)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.O.C1(C)C=CC=CC=1>[Br:23][C:16]1[CH2:17][C:18]2[C:14]([CH:15]=1)=[C:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)[C:21]([CH3:22])=[CH:20][CH:19]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1-c1cc(C(C)C)cc(C(C)C)c1)C=CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1-c1cc(C(C)C)cc(C(C)C)c1)C=C(Br)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
The obtained 4-(3,5-diisopropylphenyl)-5-methylindene (4.69 g, 15.9 mmol) was dissolved in dimethylsulfoxide (40 mL), and water (1.1 g) was added. N-Bromosuccinimide (NBS)(3.1 g, 17.5 mmol) was added at 5 to 10° C., and after elevating the temperature naturally, reaction solution was stirred for 1 hour at room temperature. Reaction solution was slowly added to mixed solution of toluene and water at room temperature, then, aqueous phase was separated. Organic layer was washed with diluted hydrochloric acid, and after aqueous phase was removed, p-toluene sulfonic acid mono hydrate (0.43 g, 2.3 mmol) was added. After reacting for 1.5 hours while heating under reflux, reaction solution was washed with aqueous solution of sodium hydroxide (1N) and water, and organic layer was extracted. Organic layer was dried over magnesium sulfate, then, solvent was distilled off under reduced pressure to obtain the crude product (5.98 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[O:9][N:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:11]=[C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[O:9][N:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cc(Cn3cc(N)cn3)on2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)on1

Procedure:
Following general procedure B followed by T, starting from 1-[3-(2-methyl-[1,3]dioxolan-2-yl)-isoxazol-5-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=378.36.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([F:45])=[C:20]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F-].[Cs+].[NH2:48][C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1.O>COCCOC.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>[NH2:48][C:49]1[CH:54]=[C:53]([C:2]2[S:3][C:4]([C:13]([C:15]3[CH:23]=[C:22]4[C:18]([C:19]([F:45])=[C:20]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:21]4[CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:17][CH:16]=3)=[O:14])=[CH:5][C:6]=2[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:52]=[CH:51][CH:50]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(N)c1
Yield: 76.4 %

Procedure:
A mixture of 6 (40 mg, 0.058 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), CsF (27 mg, 0.18 mmol), 3-aminophenylboronic acid (12 mg, 0.088 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 minutes and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 7 as a yellow amorphous solid (31 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.78-7.67 (m, 7H), 7.51-7.41 (m, 5H), 7.23 (t, J=8.0 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.85 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 4.26 (t, J=7.0 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.82 (brs, 2H), 3.70 (s, 2H), 3.48 (t, J=6.8 Hz, 2H), 1.66-1.60 (m, 2H), 1.48-1.45 (m, 2H), and 1.25 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.13, 171.26, 168.49, 149.66, 147.09, 143.16, 141.68, 140.71, 137.58, 134.19, 132.51, 132.44, 132.38, 132.14, 130.54, 130.05, 129.97, 129.54, 129.15, 129.06, 128.94, 128.58, 127.31, 127.10, 123.47, 121.43, 120.02, 119.86, 119.71, 116.81, 115.88, 115.69, 112.56, 61.31, 43.61, 37.25, 34.77, 27.36, 25.77, and 14.45; 19F NMR (376 MHZ, CDCl3) δ −174.49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:18]([OH:20])[CH3:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[ClH:1].[C:25]([O:20][CH:18]([C:16]1[S:17][C:13]2[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1)[CH3:19])(=[O:27])[CH3:26]
Reactant: Cc1nnc2n1-c1sc(C(C)O)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Product: Cl
Reaction time: 8 h

Procedure:
To a solution of 1 g of 4-(2-chlorophenyl)-2-(1-hydroxyethyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine dissolved in 20 ml of pyridine is added 1 ml of acetic anhydride under ice-cooling and then stirred overnight. After completion of the reaction, the mixture is concentrated under reduced pressure and the residue is dissolved in 30 ml of ethyl acetate. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off, the filtrate is concentrated under reduced pressure and the oily residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1-100:3). The objective fraction is concentrated under reduced pressure to give 0.9 g of 2-(1-acetoxyethyl)-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]- [1,4]diazepine.hydrochloride melting at 168°-175° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=NC(=O)c1ccc(F)c(F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-difluorobenzoyl chloride, there is obtained ethyl N-(3,4-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 406 (3), 377 (17), 194 (100), 141 (38);
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:14]([O:26][CH3:27])=[CH:15][C:16]3[N:22]([CH3:23])[C:21](=[O:24])[O:20][CH2:19][CH2:18][C:17]=3[CH:25]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([NH:33][CH3:34])=[O:32].C(O)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH3:27][O:26][C:14]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=3[C:31]([NH:33][CH3:34])=[O:32])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:25][C:17]2[CH2:18][CH2:19][O:20][C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Cl)n1)CCOC(=O)N2C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)N(C)C(=O)OCC3)ncc1C(F)(F)F
Yield: 29 %

Procedure:
2-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-Amino-N-methyl-benzamide (85 mg, 0.56 mmol;) was stirred in isopropyl alcohol (5.00 mL, 65.3 mmol;) with 10-camphorsulfonic acid (150 mg, 0.63 mmol;) at 120° C. in microwave for 30 min×3. The reaction mixture was concentrated and then extracted with DCM (20 mL) and washed with sat. NaHCO3 (20 mL) followed by water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on ISCO flash system (0-100% Hex:EtOAc) to obtain the product as one of multiple peaks by UV. The fractions were concentrated and triturated in Et2O to obtain a filterable solid (25 mg, 29%). mp: 210-212° C. (soft 150), MS (ESI+): 517 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 10.85 (s, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 7.52 (d, J=8 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 7.13 (t, J=8 Hz, 1H), 6.70 (s, 1H), 6.19 (br s, 1H), 4.42 (t, J=6 Hz, 2H), 3.92 (s, 3H), 3.40 (s, 3H), 3.04 (d, J=5 Hz, 3H), 2.76 (t, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:33].[OH-].[Na+]>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:4]2[CH:5]=[C:6]([N:9]3[CH2:14][CH2:13][S:12](=[O:15])(=[O:16])[CH2:11][CH2:10]3)[N:7]=[CH:8][C:3]=2[C:1]([NH2:2])=[O:33])=[C:18]([CH3:24])[CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 100.7 %

Procedure:
A mixture of 5-cyano-4-(4-fluoro-2-methylphenyl)-2-(1,1-dioxo-thiomorpholin-4-yl)pyridine (14.80 g, 42.85 mmol), 15 mL of toluene, and 15 mL (27.6 g, 281 mmol) of concentrated sulfuric acid was heated in a 500-mL flask at 70° C. for 12 hours. The mixture was cooled and quenched with 150 mL cold H2O. A solution of 22.8 g (570 mmol) of sodium hydroxide in 200 mL of H2O was added dropwise at 25–30° C. over 15 minutes. The precipitate was filtered, washed with H2O, and dried to afford 15.68 g (100.7%) of 4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine-3-carboxamide as a colorless solid (2 wt % toluene remains).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][C@H:13]1[NH:18][CH2:17][C@@H:16]([CH2:19][N:20]([CH3:22])[CH3:21])[O:15][CH2:14]1.C(N(CC)CC)C.CN1C(=O)CCC1>C(Cl)Cl>[NH2:7][C:6]1[CH:8]=[C:2]([N:18]2[C@H:13]([CH3:12])[CH2:14][O:15][C@@H:16]([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C[C@@H]1CO[C@H](CN(C)C)CN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: C[C@@H]1CO[C@@H](CN(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 140 °C

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2S,5R)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and NMP was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (2×) and dried (Na2SO4). Purification via chromatography on silicagel (10% MeOH in dichloromethane), afforded the desired product as a dark yellow foam. LC/MS m/z 295.2 (MH+) Rt 1.86 minutes.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]1[C@@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.[C:29]1([C:35]2[CH:48]=[CH:47][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH:45]=O)=[O:40])=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl>C(O)(=O)C.ClCCCl>[C:29]1([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:18]3[C@@H:19]4[C@H:24]([C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20]4)[CH2:15][CH2:16][CH2:17]3)=[O:40])=[CH:47][CH:48]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(NCCCCN1CCC[C@H]2c3ccccc3CC[C@@H]21)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h
Yield: 45.6 %

Procedure:
Sodium triacetoxyborohydride (340 mg, 1.6 mmol) was added to a stirred mixture of trans-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (D8a, 200 mg, 1 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (286 mg, 01.1 mmol) and acetic acid (1 drop) in 1,2-dichloroethane (10 ml) at room temperature. After stirring for 16 h, dichloromethane (20 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×25 ml) and brine (25 ml). Drying (Na2SO4) and evaporation in vacuo afforded an oil which was purified by preparative TLC on Kieselgel using 10% methanol-ethyl acetate as eluent to give the title compound as a colourless solid (200 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=1[F:32].[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:37]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=3[F:32])[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 93.6 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 3f (3.0 g, 6.8 mmol) was dissolved in 30 mL pyridine, followed by addition of 4-dimethylamino pyridine (166 mg, 1.36 mmol) and TBSCl (1.23 g, 8.2 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure before 150 mL ethyl acetate were added. The reaction mixture was washed with saturated copper sulfate solution (100 mL) and saturated sodium chloride solution (100 mL) in turn. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydro-pyran-3,4,5-triol 3g (3.75 g, white solid), yield: 99.7%.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CO>[CH2:4]([O:3][C:1]([NH:11][CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])=[CH:18][CH:19]=1)[C:21]([OH:23])=[O:22])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: BrCCCCCBr
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(Cc1ccc(OCCCCCBr)cc1)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
N-CBZ-L-tyrosine (2.06 g, 5.86 mmole) was treated with NaH (0.58 g, 12.08 mmole) and 1,5-dibromopentane (0.8 ml, 5.87 mmole) as described for 1-1 in Example 1. The crude product was dissolved in methanol and after stirring with silica gel for 0.5 hour, the solvent was removed. This was dry packed and eluted on a flash column with CHCl3 and then with 97:3:0.3 CHCl3 /CH3OH/HOAc to give pure 1-10
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].[CH3:14][Mg]Cl.C1COCC1>C1(C)C=CC=CC=1>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]
Reactant: C[Mg]Cl
Reactant: c1cc[cH-]c1
Agent: Cl[Ti]Cl
Agent: [Ti+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[c-]1cccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a well stirred slurry of titanocene dichloride (CP2TiCl2) (249 g, 1.00 mol) in toluene (2.75 L) chilled to −5° C. (internal temp) was added methyl magnesium chloride (CH3MgCl) (750 mL, 3.0M in THF, 2.25 mol) over 1 h, maintaining the temperature below 8° C. The resulting orange slurry is aged at 0-5° C. for 1 h, or until the insoluble purple Cp2TiCl2 has dissolved. A NMR was taken to confirm reaction completion (see below), then the reaction was quenched into a solution of 6% aqueous ammonium chloride (700 mL), maintained at 0-5° C. The layers were separated and the organic phase was washed with cold water (3×575 mL) and brine (575 mL), then was dried with Na2SO4 (220 g). The filtered organic layer was evaporated to 1.5 Kg (maintaining an internal temperature of 25° or less). Weight % assay by 1H NMR showed the solution to contain 187 g product (90%, 12.5 wt % solution in toluene/THF). Typically, the material was greater than 95% pure, with only traces of the starting material and monomethyl intermediate. The solution may be further concentrated to 1.0 Kg, giving a 18 wt % solution in toluene, allowing for an easier assay. However, the presence of a small amount of THF increases the stability of the compound. The material was stored under nitrogen in a sealed carboy at 0° C. 1H NMR Cp2Ti(CH3)2: δ 6.05 (s, 10H), −0.05 (s, 6H). Cp2TiCl(CH3): δ 6.22 (s, 10H), 0.80 (s, 3H). Cp2TiCl2: δ 6.56 (s, 10H). 13C NMR Cp2Ti(CH3)2: δ 113.20 (Cp2), 45.77 ((CH3)2). Cp2TiClCH3: δ 115.86 (Cp2), 50.37 (CH3). Cp2TiCl2: δ 120.18.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>O1CCCC1>[CH2:15]([N:17]([CH2:18][CH3:19])[S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])[CH3:16]
Reactant: CCNCC
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1sc(NC(C)=O)nc1C
Reaction time: 4 h

Procedure:
2-Acetamido-4methylthiazole-5-sulfonyl chloride (5.2 g) in tetrahydrofuran (100 cm3) was stirred at ambient temperature and treated portionwise with diethylamine (4.5 cm3). The mixture was stirred for 4 hours, evaporated under reduced pressure and the residue extracted into ethyl acetate (200 cm3), washed with water (2×100 cm3), dried (MgSO4) and re-evaporated under reduced pressure to give N,N-diethyl 2-acetamido-4-methylthiazole-5-sulfonamide (4.9 g). 1H NMR: δ 1.20(6H,t); 2.28(3H,s); 2.57(3H,s); 3.32(4H,q); 9.7(1H,br s); (solid).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>O.CC(C)=O>[Cl:18][C:16]1[CH:15]=[C:14]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:13]=[CH:12][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
4-Nitrophenol (2.8 g, 20.1 mmol), 2,4-dichloro-pyrimidine (3 g, 20.1 mmol), NaOH (0.8 g, 20.1 mmol) dissolved in H2O/acetone (80 ml; 1:1) are stirred at 60-65° C. for 1 h. The reaction solution is concentrated under reduced pressure and flash chromatographed (silica gel, 4.5×22 cm, AcOEt/hexane=1:4) to give the title compound of Stage 21.2 as a colorless solid: M+H=252/254; 1H-NMR (400 MHz, DMSO-d6): 8.67 (s, 1H, pyrimidinyl), 8.34 (d, 9 Hz, 2H, phenyl), 7.58 (d, 9 Hz, 2H, phenyl), 7.53 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=1:1): 0.16; m.p.=125.4-126.6° C.
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30]>CCOCC>[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30].[CH3:17][N:18]1[C:22]([C:3](=[N:2][CH3:1])[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: CN=C(Cl)c1ccc(C)cc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CN=C(c1ccc(C)cc1)c1c(C)cc(CC(=O)OC)n1C
Temperature: 25 °C
Yield: 61 %

Procedure:
N-Methyl 4-methylbenzimidoyl chloride (5.44 g, 32.5 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform (13 ml) and chlorosulfonic acid (0.38 g, 3.2 mmole). The reaction was placed under a nitrogen atmosphere and stirred at room temperature. Methyl 1,4-dimethyl-1H-pyrrole-2-acetate (5.39 g, 32.3 mmole) was added and the reaction was stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The phases were separated, and the organic phase was extracted with saturated aqueous sodium bicarbonate and water, then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting red-brown viscous liquid was dissolved in absolute ethanol and treated with 70% perchloric acid (5.1 g, 35.5 mmole). The solution was cooled and treated with ether to induce crystallization. The solid was isolated by filtration, washed with cold ethanol, and air dried to yield 7.86 g (61%) of the title compound, m.p. 119°-124° C. (dec).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])=[O:3].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:2]1([CH3:1])[O:15][CH2:14][CH2:13][O:3]1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C2(C)OCCO2)c(F)c1
Yield: 77 %

Procedure:
A solution of 5.00 g (30.00 mmol) 2-fluoro-4-methoxyacetophenone, 1.11 ml (33.00 mmol) ethylene glycol and 0.28 g (1.49 mmol) p-toluene sulfonic acid hydrate in 50 ml toluene was refluxed in a Dean-Stark apparatus for 2.5 days. After 0.5 and 1.5 days additional 1.11 ml (33.00 mmol) ethylene glycol and 0.28 g (1.49 mmol) p-toluene sulfonic acid hydrate were added. After cooling, the reaction was diluted in ether and washed with aqueous saturated NaHCO3 (two times) and aqueous 10% NaCl solution. The water phases were extracted with ether, the organic phase was dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography (SiO2; n-heptane/AcOEt=95:5) to give 4.90 g of the title compound as brown liquid (with ca 10% of starting material, seen in 1H-NMR).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[C:14]=S>>[C:9]1([CH3:12])[CH:8]=[CH:7][C:6]([CH:2]2[CH2:3][CH2:4][O:5][C:14]([NH:13][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[N:26]=[CH:25][N:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=5)[N:23]=4)=[CH:20][CH:21]=3)=[N:1]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(N)CCO)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: Cc1ccc(C2CCOC(Nc3ccc(-c4ncn(-c5ccc(OC(F)(F)F)cc5)n4)cc3)=N2)cc1

Procedure:
The title compound was prepared with 3-amino-3-(p-tolyl)propan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.020 g, 9%).