Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([C:53](O)=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)OCC.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CO)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a stirred solution of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (6.4 g, 8.13 mmol) and Et3N (1.473 mL, 10.57 mmol) in THF (80 mL) was added ethyl carbonochloridate (1.011 mL, 10.57 mmol) at 0° C. After 1 h, a solution of NaBH4 (1.538 g, 40.7 mmol) in cold water (80 mL) was added at once and stirred for additional 1 h at 0° C. Then the reaction was quenched with MeOH (5 mL), diluted with Et2O (100 mL), washed with water (2×50 mL) and brine (25 mL). The organic layer dried (Na2SO4), filtered and concentrate. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (4.5 g, 5.82 mmol, 71.6% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.74-7.70 (m, 4H), 7.46-7.35 (m, 6H), 6.48 (s, 1H), 5.90 (br. s., 1H), 4.91-4.83 (m, 2H), 4.29-4.11 (m, 2H), 3.94-3.84 (m, 1H), 3.41-3.29 (m, 3H), 2.61 (s, 3H), 2.17 (q, J=5.8 Hz, 1H), 1.94-1.87 (m, 2H), 1.87 (br. s., 1H), 1.66 (br. s., 1H), 1.59 (s, 3H), 1.58-1.40 (m, 5H), 1.33-1.26 (m, 3H), 1.26-1.21 (m, 12H), 1.09 (d, J=6.1 Hz, 3H), 1.07 (s, 9H). LCMS (M+H)=773.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[C:28]1[C:33]([Cl:34])=[CH:32][C:31]([Cl:35])=[CH:30][C:29]=1[Cl:36])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[C:28]3[C:29]([Cl:36])=[CH:30][C:31]([Cl:35])=[CH:32][C:33]=3[Cl:34])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)c1c(Cl)cc(Cl)cc1Cl
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3c(Cl)cc(Cl)cc3Cl)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.088 g, 0.318 mmol) was reacted with N-(2-azidoethyl)-2,4,6-trichlorobenzamide (0.093 g, 0.318 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2,4,6-trichlorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), δ 7.34 (s, 1H), δ 7.26 (s, 2H), δ 6.42 (s, 1H), δ 5.97 (s, 2H), δ 4.51 (s, 2H), δ 3.94 (s, 2H), δ 2.45 (t, 2H), δ 2.20 (s, 2H), δ 1.47 (m 13H), δ 1.21 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 164.7, 148.0, 135.7, 134.6, 132.9, 128.7, 128.1, 127.3, 122.3, 84.9, 53.7, 49.3, 39.9, 31.8, 29.2, 28.9, 28.2, 25.5, 22.8, 14.3 ppm; HRMS (ESI) calcd for C24H30Cl3N7O3 (M+) 569.1476. Found 569.1477, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2,4,6-trichlorobenzamide hydrochloride (0.116 g, 72% yield). 1H NMR (300 MHz, CD3OD) δ 8.36 (s, 1H), δ 7.45 (s, 2H), δ 6.46 (s, 1H), δ 4.77 (s, 2H), δ 3.97 (s, 2H), δ 2.80 (s, 2H), δ 2.48 (t, 2H), δ 1.73 (s, 2H), δ 1.62 (s, 2H), δ 1.41 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 165.5, 147.3, 136.9, 134.5, 132.7, 128.2, 128.0, 127.6, 108.6, 51.2, 39.0, 28.1, 27.7, 24.1, 23.8 ppm; HRMS (ESI) calcd for C19H22Cl3N7O (M+) 469.0951. Found 469.0941.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][CH:22]=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].N12CCC(CC1)CC2>O.CO.C(OCC)(=O)C>[C:16]([O:15][C:14]([N:13]([C@@H:10]([CH:11]=[CH2:12])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:21][CH:22]([OH:23])[C:25](=[CH2:26])[C:24]([O:28][CH3:29])=[O:27])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CC(=O)OC
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC=O)C(=O)OC(C)(C)C
Agent: C1CN2CCC1CC2
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(O)C(=C)C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-oxoethyl)carbamate (Intermediate 99, 16.1 g, 46.8 mmol), methyl acrylate (6.3 mL, 70 mmol), and methanol (about 2 mL), under nitrogen at ambient temperature, was added Quinuclidine (2.1 g, 19 mmol) as a solid. The mixture was then stirred for 1 day; analysis by TLC (15% ethyl acetate in hexanes) indicated incomplete conversion of starting material. Another 0.8 eq of quinuclidine was added every 24 hours; another 0.75 eq methyl acrylate and 1 mL methanol were added every two days. After 6 days total, the reaction was diluted with water and extracted with ethyl acetate. TLC indicated that only one extraction with about 250 mL ethyl acetate was needed to bring all the crude product into the organic layer, which was then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Normal-phase chromatography (5-30% ethyl acetate in hexanes, 220-g column, 35 minutes) afforded the desired compound (16 g, 80%, pale oil) as a mixture of diastereomers, with about 10 mol % of starting aldehyde present according to proton NMR analysis. The material was taken forward in this state.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:15]1[N:16]=[CH:17][N:18]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]CC)=[O:22])[CH:19]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:3]([C:15]1[N:16]=[CH:17][N:18]([CH:20]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([OH:23])=[O:22])[CH:19]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCc1cn(C(C(=O)OCC)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cn(C(C(=O)O)c2ccccc2)cn1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Solid NaOH (0.9 g, 22.6 mmol) was added to a solution of ethyl (±)-4-dodecyl-α-phenyl-1H-imidazole-1-acetate (4.5 g, 11.3 mmol) in 150 mL 95% ethanol. The resulting solution was stirred for 2 hours and then concentrated in vacuo. The residue was partitioned between water and ether, the aqueous layer was acidified with concentrated HCl, and extracted with dichloromethane. The dichloromethane solution was dried over MgSO4, filtered, and concentrated to give a white solid (2.53 g, 55%); mp 110°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=O)[C:25]=2[CH:24]=[CH:23][C:22]1=[O:32].C1C=CC=CC=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH:26]1[CH2:27][CH2:28][CH2:29][C:30]3[NH:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1=3)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2c([nH]1)CCCC2NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a flask was added N1-(6-chloro-1,2,3,4-tetrahydro-acridin-9-yl)-propane-1,3-diamine (116 mg, 0.40 mmoL), 7,8-dihydro-1H,6H-quinoline-2,5-dione (85 mg, 0.52 mmoL), benzene (4 mL) and one drop of acetic acid, and the resulting mixture as heated to reflux under nitrogen. The water generated from the reaction was removed by Dean-Stark apparatus. After refluxing for 24 h, the benzene was distilled off and methanol (2 mL) was added, followed by sodium borohydride (30 mg, 0.80 mmoL). After stiring at room temperature for 24 h, the reaction was stopped and concentrated. The mixture was treated with saturated sodium bicarbonate and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride twice. The combined methylene chloride extract was combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative TLC using 15% MeOH/1% ammonium hydroxide in methylene chloride to give the desired product (102 mg, 0.23 mmoL, 58%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)[CH3:2].[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([O:12][CH3:13])[CH:6]=1)=[O:14])[CH3:16]
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCN(CC)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)c(OC)c1

Procedure:
The title product was prepared from N,N-diethyl-4-hydroxy-3-methoxy-benzamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (58%, colorless oil). HPLC-MS: m/z=357.1 (M+1); Rt: 3.64 min.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]([OH:28])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][CH2:26]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]2[CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]3[CH2:25][CH2:26][O:28]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc(F)c1C#N
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: Cc1c(C2CN3CCN(C(=O)OC(C)(C)C)CC3CCO2)ccc(F)c1C#N
Temperature: 100 °C

Procedure:
tert-Butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (2.61 g, 6.41 mmol) and dissolved in benzene (60 mL) and added cyanomethylene tributyl phosphorane (2.78 g, 11.5 mmol). The mixture was placed into four separate 20 mL microwave tubes then heated at 100° C. overnight. The reaction mixtures were combined, concentrated then purified by MPLC chromatography using a 330 g ISCO Redi-Sep column and 5% acetone-95% DCM solvent system. Under these purification conditions was separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate cis diastereomers from the trans diastereomers LC-MS (IE, m/z): 334 [(M-56)+1]+; The cis-diastereomers were further separated to S,R and R,S diastereomers using the following conditions: Chiral IC column: 30×250 mm, 20% MeOH:/CO2, 70 mL/min, 100 bar, 50 mg/ml in MeOH, 35° C., 330 nm: cis-diastereomer A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.88 (dd, J=8.7, 6.2 Hz, 1H), 7.04 (t, J=8.6 Hz, 1H), 4.83 (s, 1H), 4.03 (d, J=12.9 Hz, 1H), 3.86 (t, J=11.3 Hz, 1H), 3.79-3.96 (b, 2H), 2.93 (q, 2H), 2.83 (b, 1H), 2.56-2.63 (m, 4H), 2.53 (s, 3H), 1.78-1.87 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1]OC(C)(C)C.[CH2:7]([S:13][CH2:14][CH:15]=[CH2:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:7]([S:13][CH:14]=[CH:15][CH2:16][Cl:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CCSCCCCCC
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: CCCCCCSC=CCCl
Temperature: 25 °C

Procedure:
Tert-butyl hypochlorite (2.06 g, 19.0 mmol) is added dropwise at -50° to a solution of 3-hexylthio-1-propene (3.0 g, 19.0 mmol) in 20 ml of methylene chloride. The mixture is allowed to warm to RT and is then stripped of solvent to give 3-hexylthio-2-propenyl chloride.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1C
Product: COc1cccc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 82 %

Procedure:
4-Hydroxy-N-(3-methoxyphenyl)-2-methyl-2H -naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 3-methyoxy-aniline. Yield: 82% of theory; m.p. 242°-244° C (decomp.; from xylene).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].S(=O)(=O)(O)O>O.CO.C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][C:12](=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 130 °C

Procedure:
Acetophenone (30 grams; 0.25 mol), methylbenzoate (130 grams, 1.0 mol), sodium methoxide (17.3 grams; 0.32 mol) and xylene (350 ml) were placed into a four necked round bottom one liter flask, equipped with stirrer, nitrogen addition adapter, thermometer and Oldershaw column connected with a distillation head and a trap. The solution was heated under a blanket of nitrogen to a temperature of about 130° C. At about 130° C., the mixture of xylene and methanol begins to come off the reaction mixture. Upon cooling the reaction mixture is acidified by adding sulfuric acid (21 ml) in water (100 ml). Once the material goes into solution it is transferred to a separatory funnel and the aqueous layer is removed. The xylene layer is washed with water (100 ml of a 10% solution). Then it is stirred at 120° C. and 15 mm Hg. The yield of dibenzoyl methane was 94 weight percent having a purity of 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=O)[C:6]=2[CH:16]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:39]3[CH2:38][CH2:37][CH:36]([N:28]([CH2:27][C:24]4[N:23]=[CH:22][C:21]5[O:20][CH2:19][CH2:18][O:17][C:26]=5[CH:25]=4)[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:41][CH2:40]3)[C:6]=2[CH:16]=1
Reactant: O=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Yield: 42 %

Procedure:
A mixture of (6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)acetaldehyde (89 mg, 0.372 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (117 mg, 0.334 mmol) in chloroform (5 ml) and MeOH (0.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (212 mg, 1.002 mmol). The reaction was stirred for 1 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 10% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound as a yellow oil (81 mg, 42%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[OH:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH:23]([OH:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Product: CCOC(=O)C(O)Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1
Yield: 42.8 %

Procedure:
The title compound (1.06 g, 43%) was prepared as a pale yellow liquid from 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.8 g, 5.9 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (1.36 g, 6.49 mmol) by an analogous procedure to that described in example 6 (Method B).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:5])[CH3:4].Cl[CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>O1CCCC1.CN(C)C=O>[C:3]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][CH:13]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCc1ccc(O)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(COC(C)=O)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
0.53 g (132 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 20 g (120 mmol) of (4-hydroxy-phenyl)-methyl acetate diluted in 100 ml of tetrahydrofuran and 100 ml of dimethylformamide. The reaction mixture is stirred at room temperature, and then 15 ml (132 mmol) of 1-chloromethoxy-2-methoxy-ethane is added dropwise. After stirring at room temperature for 2 hours, then adding water, the reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. After evaporation of the solvents, 25 g (86%) of [4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate is obtained in the form of a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:21][C:22]([OH:24])=O)[C:9]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:41][C:42]([NH2:44])=[NH:43].C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:21][C:22]([NH:43][C:42]([NH2:44])=[NH:41])=[O:24])[C:9]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)O)CC1
Reactant: N=C(N)N
Agent: CN(C)c1ccncc1
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)NC(=N)N)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 145.2 %

Procedure:
To a solution of 0.91 g (2.8 mmol) [2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetic acid in 28 mL anhydrous DMF was added 2.27 g (14 mmol) carbonyldiimidazole. The reaction was stirred at room temperature for 50 min, upon which time was added 2.52 g (14 mmol) guanidine carbonate, 0.17 g (1.4 mmol) 4-dimethylaminopyridine, and 2.83 g (28 mmol) triethylamine. The reaction was stirred at room temperature over 16 hr. The solution was filtered to remove the precipitate that formed, was diluted with ethyl acetate, and was washed three times with brine. Drying over MgSO4 and concentration afforded 1.49 g of N-{2-[2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetyl}-guanidine as a yellow-brown oil. The product was observed to contain DMF by 1H NMR. However, it was used in the next step without further purification.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][C@H:5]1[S:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].OC1C=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][S:22][C@H:5]1[O:4][C:3]1[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[CH:31][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C(C)=O)cc1
Yield: 47 %

Procedure:
If the procedure described in Preparation LXXXI is followed starting from 380 mg (0.882.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 100 mg (73.5.10-3 mol) of 1-(4-hydroxyphenyl)ethanone and 1.47 ml of a 0.1M solution of boron trifluoride etherate in methylene chloride, 140 mg (yield: 47%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:27][C:28]#[N:29])[CH2:21][N:20]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:19]4)[CH:17]=3)[N:10]3[CH:30]=[CH:31][N:32]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C([O-])(O)=O.[Na+].[Cl:38]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:38][C:30]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:27][C:28]#[N:29])[CH2:21][N:20]([CH2:22][C:23]([F:24])([F:26])[F:25])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:32][CH:31]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(-c2cc3ncc(Cl)n3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (Example 71, 100 mg, 0.227 mmol) in DCM (1.5 mL) was added saturated NaHCO3 (1.0 mL) followed by N-chlorosuccinimide (46.3 mg, 0.340 mmol) in one portion. The biphasic mixture was vigorously stirred at ambient temperature for 17 hours and was diluted with DCM (2 mL). The solution was washed with H2O, dried over Na2SO4 and eluted through a silica gel plug (EtOAc elution). The solution was concentrated, the residual glass was dissolved in minimal DCM and hexane was added to afford a granular suspension. The suspension was concentrated and the residual solid was washed with warm 25% EtOAc/hexanes and dried in vacuum to afford the title compound (22 mg, 20% yield) as an ivory white powder. MS (apci) m/z=476.1 (M+H).