Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:38])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:13]3[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][N:18]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:7]=1)=[O:4].Br[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[N:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:20]1[C:13]2[C:12]([C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:1])=[CH2:38])[CH:11]=[CH:10][CH:9]=3)=[N:17][CH:16]=[N:15][C:14]=2[N:18]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[CH:19]=1
Reactant: Brc1ccccn1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(B2OC(C)(C)C(C)(C)O2)cn3COCC[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2ccccn2)cn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-N-[3-[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]prop-2-enamide (200 mg, 0.370 mmol) in N,N-dimethylformamide (3.0 mL) under nitrogen, was added Pd(dppf)Cl2CH2Cl2 (16 mg, 0.020 mmol), 2-bromopyridine (60 mg, 0.38 mmol), and a solution of sodium carbonate (120 mg, 1.13 mmol in water, 1 mL). The resulting solution was stirred for 2 hours at 80° C. before being cooled and extracted with ethyl acetate (×3). The organic layers were combined, washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-100% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-(pyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C27H32N5O2Si [M+H]+: 486, found 486.
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([OH:32])[C@H:24]([O:29][CH2:30][CH3:31])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C([SiH](CC)CC)C.C(OCC)(=O)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH2:30]([O:29][C@@H:24]([C@H:23]([OH:32])[C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][CH3:8])[CH:12]=2)=[CH:18][CH:19]=1)[C:25]([O:27][CH3:28])=[O:26])[CH3:31]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNC)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.7 %

Procedure:
21 g (47.3 mmol) of methyl (2S,3R)-3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxy-3-hydroxypropionate, 8.76 ml (54.9 mmol) of triethylsilane in 300 ml of trifluoroacetic acid are introduced into a round-bottomed flask and under a nitrogen stream. The reaction medium is stirred for 4 hours at room temperature. Ethyl acetate is then added and the mixture is neutralized with sodium hydroxide. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. 19.6 g (100%) of the expected crude product are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[CH:13][C:14]3[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:15]=3)[N:11]=[C:4]2[N:3]=1>[Pd].CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]([CH2:19][C:20]([F:23])([F:21])[F:22])[N:17]=[C:16]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[N:15]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc2n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)n2nc(CCc3nc(N4CCCC4)nn3CC(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.5 %

Procedure:
A mixture of 5,7-dimethyl-2-(2-(3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidine (19 mg, 48.4 μmol, Eq: 1.00) and palladium on carbon 10% (5.15 mg, 4.84 μmol, Eq: 0.1) in methanol (15 ml) was stirred for 6 hours at 25° C. under hydrogen atmosphere. Evaporation of the solvent afforded 5,7-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrimidine (19 mg/99.5%) as a white solid. MS: m/z=395.5 (M+H+), mp: 180.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[OH:24][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Reactant: C#CCCCO
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CCCCO)c1

Procedure:
Sonogashira reaction of bromide 57 with 4-pentyn-1-ol gave tert-butyl 3-(3-(5-hydroxypent-1-ynyl)phenyl)propylcarbamate as yellow oil. Yield (0.653 g, 59%): 1H NMR (400 MHz, CDCl3) δ 7.17-7.23 (m, 3H), 7.08 (d, J=7.2 Hz, 1H), 4.53 (bs, 1H), 3.83 (t, J=6.0 Hz, 2H), 3.10-3.18 (m, 2H), 2.60 (t, J=7.8 Hz, 2H), 2.54 (t, J=7.0 Hz, 2H), 1.83-1.90 (m, 2H), 1.74-1.82 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])O[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[CH2:18]([CH2:20][NH2:21])[OH:19]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[N:21]([CH2:20][CH2:18][OH:19])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: NCCO
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2o1
Solvent: O
Product: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1CCO
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of the product from example 42 step (i) (1 g) and ethanolamine (10 ml) was stirred at 90° C. for 14 hours. The mixture was diluted with water (10 ml) and the solid filtered. The solid was further washed with water and then dichloromethane to leave the subtitle product as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.CC(O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[C:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:33]1[CH2:38][CH2:37][CH:36]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH2:14][CH2:15]2)[CH2:35][CH2:34]1
Reactant: O=C1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: COc1ccc2cc(N3CCNCC3)ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2cc(N3CCN(C4CCC(c5c[nH]c6ccc(F)cc56)CC4)CC3)ccc2c1
Temperature: 23 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To 400 mg (1.66 mmol) of 1-(6-methoxy-naphthalen-2-yl)-piperazine in 40 mL of CH2Cl2 and 100 mg of glacial HOAc at 23° C. was added 384 mg (1.66 mmol) of 4-(5-fluoro-1H-indol-3-yl)-cyclohex-3-enone followed by 216 mg, (1.89 mmol) of Na(OAc)3BH. After stirring at 23° C. for 12 hours, the reaction mixture was transferred to a separatory funnel and partitioned between water and CH2Cl2. The organics were washed with brine, dried over MgSO4, and chromatographed on silica gel eluting with 20:1 EtOAc:2 M NH, in MeOH. The product fractions were pooled, stripped, and treated with 115 mg (1.3 mmol) of (CO2H)2 in absolute EtOH to give 640 mg (1.40 mmol, an 84% yield) of the oxalate salt of the title compound as a white crystalline solid. mp: 200-203° C.; MS (ES) m/z 458 (M)+.
Reaction SMILES: C([Si]([O:8][CH2:9][CH:10]1[O:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:14]1[CH:10]([CH2:9][OH:8])[CH2:11][C:12]2[CH:22]=[CH:21][C:20]3[C:15]([C:13]1=2)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2ccc3ccccc3c2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCC1Cc2ccc3ccccc3c2O1

Procedure:
Treatment of (±)-tert-butyl(2,3-dihydronaphtho[1,2-b]furan-2-ylmethoxy)dimethylsilane (2.70 g; 8.59 mmol) with tetrabutylammonium fluoride (9.4 mL, 1.0 M solution in tetrahydrofuran) generally according to the procedure described for Intermediate 6 gave (±)-2,3-dihydronaphtho[1,2-b]furan-2-ylmethanol. Treatment of the alcohol with p-toluenesulfonyl chloride (1.64 g, 8.59 mmol), 4-(dimethylamino)pyridine (0.105 g, 0.86 mmol), and triethylamine (1.67 g, 12.89 mmol) generally according to the procedure described for Intermediate 14 provided (±)-2,3-dihydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate. To a solution of the tosylate in dimethylsulfoxide (50 mL) was added sodium azide (0.558 g, 8.59 mmol) and the reaction mixture was allowed to stir at 70° C. for 12 h, cooled to room temperature, diluted with water (200 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts were washed with water (4×75 mL), saturated aqueous sodium chloride (75 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 1.38 g (71%) of (±)-2-(azidomethyl)-2,3-dihydronaphtho[1,2-b]furan as a colorless oil. Rf=0.46 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C13H11N3O.0.1H2O: C, 68.77; H, 4.97; N, 18.51. Found: C, 68.4; H, 4.62; N, 18.12.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:31]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
[8-(2-methoxy-5-trifloromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 3-(4-methylpiperazin-1-yl)phenylamine (0.096 g, 0.5 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 86%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (d, J=6.4 Hz, 1H), 7.91 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.53 (d, J=6.4 Hz, 1H), 7.26-7.19 (m, 2H), 7.12 (d, J=7.7 Hz, 1H), 7.04 (d. J=7.7 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 6.83 (s, 1H), 6.58 (d, J=7.7 Hz, 1H), 3.88 (s, 3H), 3.28-3.22 (m, 4H), 2.64-2.55 (m, 4H), 2.37 (s, 3H). MS=483 (MH)+.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1.[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>C1COCC1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[CH3:11])[OH:15]
Reactant: Cc1ccccc1C=O
Reactant: BrCCC1OCCO1
Agent: II
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)CCC1OCCO1
Temperature: 63 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Mg turnings (134.0 mg, 5.6 mg-at.) and catalytic amount of iodine in 20 mL THF was added dropwise 2-(2-bromoethyl)-[1,3]dioxolane (500.0 mg, 2.8 mmol) with heating over a period of 30 min. After stirring the mixture for 30 min at 63° C. the reaction was cooled to −30° C. and 2-methyl-benzaldehyde (275.0 mg, 2.5 mmol) was slowly added as a solution in 5 mL THF. The temperature was maintained at −30° C. for 1 h and then slowly raised to room temperature over a period of 3 h. The excess Grignard reagent was destroyed by the careful addition of saturated aqueous NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL). After evaporation of the solvent, the product was isolated by flash column chromatography eluting with 0 to 50% EtOAc/hexanes affording 290 mg of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][N:4]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2ccccc2)c1Cl
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1Cl
Yield: 72.7 %

Procedure:
4-Chloro-3-hydroxy-5-phenylisoxazole (0.58 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.48 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1 (a) to obtain the title compound (0.73 g, 72%) as colorless crystals.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:11]([O:12]C(=O)C)[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24](=[O:34])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)[O:16][C@@:7]([CH2:35][O:36]C(=O)C)([CH2:8][O:9]2)[C@H:6]1[O:40]C(=O)C)(=O)C.C[O-].[Na+]>CO.O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@:10]23[O:16][C@@:7]([CH2:35][OH:36])([CH2:8][O:9]2)[C@@H:6]([OH:40])[C@H:5]([OH:4])[C@H:11]3[OH:12])=[CH:18][C:19]=1[C:24]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH3:33])=[CH:29][CH:30]=1)=[O:34]
Reactant: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzoyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (see Example 11 for preparation; 65 mg, 0.10 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was added sodium methoxide in methanol (25% wt) until pH 12 was obtained and the resulting mixture was stirred at room temperature. After 16 hours, the reaction mixture was neutralized by the addition of Dowex Monosphere 650C (H) cation exchange resin until the pH of the solution was <7, filtered and concentrated under reduced pressure. The resulting material was precipitated from ethyl acetate and heptanes and the resulting white solid was washed with heptane 2 times and dried under reduced pressure to yield the desired product (44.5 mg, 94% yield). MS (LCMS) 451.1 (M+H+; positive mode) 1H NMR (400 MHz, METHANOL-d4) delta ppm 1.40 (t, J=6.9 Hz, 3H), 3.55 (d, J=8.0 Hz, 1H), 3.60 (d, J=7.4 Hz, 1H), 3.65 (t, J=8.1 Hz, 1H), 3.67 (d, J=12.5 Hz, 1H), 3.77 (d, J=8.0 Hz, 1H), 3.83 (d, J=12.5 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 4.14 (d, J=7.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.65 (dd, J=8.4, 2.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H). HRMS calculated for C22H23O8Cl (M) 450.1081. found 450.1079.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[Cl:16]N1C(=O)CCC1=O>>[Cl:16][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:7]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1ccc2cc(S(N)(=O)=O)ccc21
Product: CCn1cc(Cl)c2cc(S(N)(=O)=O)ccc21
Yield: 36.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 77, 1-ethyl-1H-indole-5-sulfonamide (Intermediate 56, 50 mg, 0.22 mmol) and N-chlorosuccinimide (36 mg, 0.27 mmol) were converted to the title compound (21 mg, 35%). 1H NMR (DMSO-d6) δ 7.99 (d, J=1.3 Hz, 1H), 7.81 (s, 1H), 7.77-7.71 (m, 1H), 7.70-7.64 (m, 1H), 7.22 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H); MS (ESI+) m/z 259.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1.[ClH:35]>CO>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([C@@H:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1.[ClH:35]
Reactant: COCCCCC(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Solvent: CO
Product: COCCCCC(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CNCCO1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
(2S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypentyl)morpholine-4-carboxylate from Step 2 was dissolved in 1 M HCl in MeOH and stirred at 50° C. for 10 min, the solvent was removed under reduced pressure to give (2S)-2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypentyl)morpholine as its HCl salt in quantitative yield. MS m/z 494 (M+Na)+.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>>[CH2:20]([O:19][C:17]([C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[CH2:18])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1coc(Cl)n1
Product: C=C(OCC)c1nc(C(=O)OCC)co1

Procedure:
Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate was prepared using the procedure described in Example 33(a), starting from ethyl 2-chlorooxazole-4-carboxylate (10.5 g, 59.8 mmol) and tributyl(1-ethoxyvinyl)stannane (24 ml, 65.8 mmol), The product was purified with flash-chromatography. Yield 10.3 g. 1H-NMR (400 MHz; CDCl3): δ ppm 1.23-1.46 (m, 6H), 3.94-3.99 (m, 2H), 4.36-4.42 (m, 2H), 4.8 (d, 1H), 5.33 (s, 1H), 8.19 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylpropanamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and hydrocinnamoyl chloride in a similar manner as described above to give a white solid (53% yield). 1H-NMR (CDCl3): δ 8.43 (s, 1H), 7.58 (m, 1H), 7.28-7.21 (m, 5H), 7.20-7.15 (m, 2H), 5.51 (d, 1H), 5.05 (m, 1H), 3.00 (t, 2H), 2.62 (m, 2H), 2.58-2.43 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.67 (m, 1H); MS m/z 397 (M−1).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[N:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCC(c1ccccc1)N1CCOCC1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(c2ccccc2)N2CCOCC2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-morpholin-4-yl-2-phenyl-ethylamine and DIEA to give 2-(2-morpholin-4-yl-2-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 445 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](N)[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CCC(C#N)c1cccc(Br)c1
Product: CCC(C1=NCCN1)c1cccc(Br)c1
Temperature: 130 °C

Procedure:
rac-2-[1-(3-Bromo-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from 2-(3-bromo-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b) but the reaction mixture was heated under microwave irradiation to 130° C. for 1 hour: colourless powder; MS (ISP): 269.0 and 267.0 ((M+H)+.).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>CN(C)C=O.O.CCCCCC>[Br:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]
Reactant: BrCCCCCCBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1CCCCN1CCCCCCBr
Yield: 18.4 %

Procedure:
Following the procedure of Example 1, sodium hydride (3.63 g of 50% dispersion in oil, 0.15 mole), 1,6-dibromohexane (23.07 ml, 0.15 mole) and 2-piperidone (7.5 g, 0.076 mole) were reacted in dimethylformamide. The filtered, concentrated reaction mixture was taken up in 200 ml of water and 200 ml of hexane. The hexane layer was separated and evaporated to an oil. The oil was chromatographed on silica gel using ethyl acetate as eluant and tlc monitoring. Clean product-containing fractions were combined and evaporated to yield 1-(6-bromo-1-hexyl)-2-piperidone as an oil (3.66 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].[Br:11][C:12]1[CH:25]=[CH:24][C:15]([NH:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18])=[CH:14][CH:13]=1>C(O)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][S:17]([C:20]2[C:21](=[O:22])[O:10][C:3]3[C:4]([CH:5]=2)=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])(=[O:19])=[O:18])=[CH:24][CH:25]=1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: O=Cc1cccc(Cl)c1O
Solvent: CC(=O)O
Product: O=c1oc2c(Cl)cccc2cc1S(=O)(=O)Nc1ccc(Br)cc1

Procedure:
A solution of 3-chlorosalicylaldehyde (1 mmol) and 4-bromoanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 202-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([OH:26])=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][NH:43][S:42]1(=[O:47])=[O:46])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([N:43]5[S:42](=[O:47])(=[O:46])[N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:45][CH2:44]5)=[O:26])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNS1(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)S1(=O)=O

Procedure:
tert-Butyl 5-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetyl}-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (from Example 4) and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid tert-butyl ester following General Procedure C.