Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](O)=[O:22])=[CH:15][CH:14]=1.S(Cl)([Cl:31])=O>ClCCl.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:31])=[O:22])=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
To (0.05 mol) of 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid in dichloromethane solution (500 ml) and chilled in an ice bath is added thionyl chloride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzoyl choride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([O:16][CH2:25][CH:24]=[CH2:23])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.5 g, 3.6 mmol) and Cs2CO3 (2.26 g, 6.9 mmol) in DMF (20 mL), allyl bromide (0.6 mL, 3.9 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 40 h at RT. DMF was evaporated. The residue was dissolved in EtOAc and washed with aq. HCl 1 N, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:6) to give the title compound. MS (LCMS): 167.9 [MH-Boc]+, 290.0 [M+Na]+.
Reaction SMILES: [ClH:1].Cl.Cl.N1C=C(CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.Cl.N1C=C(CN2C3C=CC(C#N)=CC=3CN(S(C)(=O)=O)[C@H](CC3C=CC=CC=3)C2)N=C1.[C:71]1([S:77]([Cl:80])(=[O:79])=[O:78])[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.Cl.Cl.Cl.Cl.[C:85]([C:87]1[CH:88]=[CH:89][C:90]2[N:96]([CH2:97][C:98]3[N:99]=[CH:100][NH:101][CH:102]=3)[CH2:95][C@@H:94]([CH2:103][C:104]3[CH:105]=[N:106][CH:107]=[CH:108][CH:109]=3)[N:93](S(C)(=O)=O)[CH2:92][C:91]=2[CH:114]=1)#[N:86]>>[ClH:80].[ClH:1].[C:85]([C:87]1[CH:88]=[CH:89][C:90]2[N:96]([CH2:97][C:98]3[N:99]=[CH:100][NH:101][CH:102]=3)[CH2:95][C@@H:94]([CH2:103][C:104]3[CH:105]=[N:106][CH:107]=[CH:108][CH:109]=3)[N:93]([S:77]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)(=[O:79])=[O:78])[CH2:92][C:91]=2[CH:114]=1)#[N:86]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1
Agent: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Agent: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1ccccc1)[C@H](Cc1cccnc1)CN2Cc1c[nH]cn1
Yield: 2 %

Procedure:
Example 375 was prepared as a solid in 2% yield from Compound B of Example 350 as described for Compound C of Example 350 using benzenesulfonyl chloride, and Compound D of Example 350.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C([Li])CCC.[CH3:15][S:16]SC>C(OCC)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([S:16][CH3:15])[S:3][C:4]=1[CH3:9]
Reactant: Cc1sc(Br)c(C)c1Br
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1sc(C)c(Br)c1C
Temperature: -70 °C

Procedure:
20.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 300 ml. of anhydrous ehtyl ether. The resulting solution was cooled to -70° C. with stirring under argon. 32 Ml. of a 2.4 M solution of n-butyl lithium was added slowly and the solution was warmed to -32° C. for 10 minutes and then cooled again to -70° C. 7.5 G. of dimethyldisulfide was added slowly while the temperature was maintained at -70° C. The resulting solution was warmed to room temperature and stirred for 2 hours then poured into ice water, stirred for 15 minutes, and extracted with ethyl ether. The combined ether extracts were washed with water, 5% sodium carbonate, and saturated sodium chloride solution; dried over sodium sulfate, filtered and evaporated to yield 3-bromo-2,4-dimethyl-5-(methylthio)thiophene.
Reaction SMILES: COC(C1C=C(O[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].FC1C=CC(CS(CC2C=CC(F)=CC=2)(=O)=O)=CC=1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Agent: O=S(=O)(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 4-fluorophenyl methylsulfone. 1H NMR (400 MHz, CDCl3) δ 7.89-7.94 (m, 2 H) 7.26-7.27 (m, 1 H) 7.22 (d, J=1.26 Hz, 1 H) 7.02-7.11 (m, 2 H) 3.69-3.76 (m, 1 H) 3.60 (dd, J=11.87, 7.58 Hz, 1 H) 3.16 (d, J=16.42 Hz, 1 H) 3.07 (s, 3 H) 2.78 (d, J=16.67 Hz, 1 H) 1.86 (dd, J=7.58, 5.81 Hz, 1 H) 1.57 (s, 9 H) 1.44 (s, 3 H); LCMS for C26H26O7S m/z 435.00 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[CH2:18][CH:17]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[O:16][N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[CH2:18][CH:17]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:3][C:4](=[O:7])[O:5][N:48]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[O:16][N:15]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.85 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.46 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.22 g, 43%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[CH:2]
Reactant: CCCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2ccc(CCCCC)cc2)cc1
Temperature: -10 °C

Procedure:
In an analogous manner to Example 1, solution of 4-(2,2-dibromovinyl)-4'-pentylbiphenyl in absolute tetrahydrofuran was placed in a sulphonation flask and treated within 5 minutes with a solution of butyl lithium in hexane. After completion of the addition, the mixture was warmed to -10° C. within 10 minutes, then poured into water and extracted with diethyl ether. The organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography of the residue on silica gel with hexane and recrystallization from methanol gave 4-ethynyl-4'-pentylbiphenyl as colourless crystals (purity 99.5%); m.p. (C-N) 56.4° C., cl.p. (N-I) 82.7° C.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]/[N:19]=[C:20](\[CH3:23])/[CH:21]=O)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:4](=[O:9])[C:5]([C:6]([OH:7])=[O:8])=[CH:21][C:20]([CH3:23])=[N:19]2)=[CH:16][CH:17]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: C/C(C=O)=N\Nc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.9 %

Procedure:
A suspension of 2,2-dimethyl-1,3-dioxane-4,6-dione (0.71 g, 4.93 mmol) and (E)-2-(2-(4-fluorophenyl)hydrazono)propanal (0.889 g, 4.934 mmol) in toluene (20 mL) was treated with acetic acid (5 drops) and with piperidine (5 drops). The reaction mixture was then stirred at room temp for 17 hours. The precipitated condensation/cyclization product was filtered off and thoroughly washed with light petroleum to afford 0.709 g (58%) of the desired product. LRMS (ESI pos) m/e 249.1 (M+1). 1H-NMR (400 MHz, CD3OD) δ 7.96 (s, 1H), 7.61 (m, 2H), 7.24 (t, 2H), 2.45 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −115.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:27]=[CH:26][C:17]3[O:18][C:19]([CH3:25])([CH3:24])[C@@:20]4([CH3:23])[O:22][C@H:21]4[C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]([OH:36])=[N:30]1.N1C=CC=CC=1>O1CCOCC1>[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]([O:36][C@H:21]2[C@@:20]([OH:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18][C:17]3[CH:26]=[CH:27][C:14]([S:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:13])=[O:12])=[CH:15][C:16]2=3)=[N:30]1
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H]2O[C@]2(C)C(C)(C)O3)cc1OC
Reactant: Cn1nc(O)ccc1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H](Oc2ccc(=O)n(C)n2)[C@](C)(O)C(C)(C)O3)cc1OC
Yield: 42.8 %

Procedure:
(3S,4S)-3,4-Dihydro-6-(3,4-dimethoxyphenyl)sulphonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (3.0 g) (see Preparation 25) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (2.0 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (30 ml), pyridine (0.61 g) was added and the mixture heated under reflux (a calcium chloride drying tube was attached to the flask) for 2 days. The solvent was removed under reduced pressure, the residue stirred with 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the crude product chromatographed on silica eluting with 2.5:97.5 methanol: dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-6-(3,4-dimethoxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.7 g) as a yellow foam.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([F:17])([F:16])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)C([O:25][CH2:26][CH3:27])=C)CCC.[O:36]1CCO[CH2:38][CH2:37]1>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>[F:16][C:5]1([F:17])[C:6]2[CH:7]=[C:8]([C:37](=[O:36])[CH3:38])[CH:9]=[CH:10][C:11]=2[C:12]2[C:4]1=[CH:3][C:2]([C:26](=[O:25])[CH3:27])=[CH:14][CH:13]=2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc2c(c1)C(F)(F)c1cc(C(C)=O)ccc1-2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-difluoro-9H-fluorene (900 mg, 2.500 mmol), Tributyl(1-ethoxyvinyl)tin (3.38 mL, 10.00 mmol) and Pd(Ph3P)4 (289 mg, 0.250 mmol) in 1,4-dioxane (25 mL) were degassed with nitrogen for 10 min then it was heated at 90° C. for overnight under nitrogen. The reaction mixture was cooled to room temperature and 15 mL of 10% HCl was added then stirred for 1 h. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine. The organics were dried (Na2SO4) and concentrated. The crude material was purified on silica gel using 0-100% ethyl acetate in hexane. The desired fractions were concentrated to give a white solid.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3>[Pd]>[N:7]1[C:8]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=2)=[CH:9][N:10]2[C:6]=1[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][C:4]=1[O:13][CH2:12][CH2:11]2
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A solution of [5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol (67 mg, 0.17 mmol) in IMS was degassed then treated with Pd/C (10% wt. 120 mg) before being stirred at RT under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Celite®, washing with DCM, the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 7% methanol in DCM) to give 315 as a white solid (13 mg, 24%). LCMS: RT=3.79 min, [M+H]+=326. 1H NMR 400 MHz (DMSO-d) δ: 8.42 (1 H, dd, J=8.03, 1.74 Hz), 7.91 (1 H, s), 7.33 (1 H, ddd, J=8.16, 7.12, 1.77 Hz), 7.16-7.16 (1 H, m), 7.06 (1 H, dd, J=8.18, 1.21 Hz), 5.86 (1 H, t, J=6.61 Hz), 5.21 (1 H, t, J=6.03 Hz), 4.52 (4 H, q, J=5.81 Hz), 4.42 (2 H, d, J=6.00 Hz), 1.48 (6 H, d, J=6.61 Hz)
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]12[CH2:15][NH:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:10]2[CH2:11][CH:12]3[CH:8]([CH2:15][NH:14][CH2:13]3)[CH2:9]2)[CH:3]=1
Reactant: C1NCC2CNCC12
Reactant: Fc1cccnc1
Product: c1cncc(N2CC3CNCC3C2)c1

Procedure:
Prepared by heating 3-fluoropyridine and 3.7-Diazabicyclo[3.3.0]octane in an autoclave in the absence of solvent at 180° C. for 24 hours. Workup-procedure A/B.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[OH-].[Na+].O1CCOCC1>O>[F:3][CH:2]([O:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][CH:9]=1)[F:4]
Reactant: FC(F)Cl
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(OC(F)F)c1
Temperature: 68 °C
Reaction time: 0.75 h

Procedure:
260 Parts by weight of chlorodifluoromethane are passed, over 1.5 hours, into a stirred mixture of 221 parts by weight of m-cresol, 412 parts by weight of sodium hydroxide, 600 parts by volume of 1,4-dioxane and 500 parts by volume of water, at 67°-70° C. After stirring for 45 minutes at 68° C., the reaction mixture is cooled, diluted with 1,000 parts by volume of water and extracted four times with 200 parts by volume of ether. After drying the ether phase, concentrating under reduced pressure and distilling, 172 parts by weight of m-tolyl difluoromethyl ether of boiling point 64°-67° C./24.7 mbar are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([CH3:16])[CH2:3]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](O)=[O:27])=[N:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:9]([N:7]1[CH2:8][CH:2]([NH:1][C:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][N:18]=2)=[O:27])[CH2:3][N:4]([CH3:16])[CH2:5][CH2:6]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN1CCN(Cc2ccccc2)CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine (1.0 g) in dichloromethane (20 ml), 1H-indazole-3-carboxylic acid (740 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (877 mg) are added, and the resulting mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with water and 10% aqueous sodium hydroxide solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.9 g) as an oil. The free base thus obtained is converted to the hemifumarate of the title compound in a usual manner, m.p. 192°-194° C. (recrystallized from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:26])([CH2:24][OH:25])[C:21](O)=[O:22])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:4]=2[CH:3]=1.C(O)C.O.C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:26])([CH2:21][OH:22])[CH2:24][OH:25])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:4]=2[CH:3]=1
Reactant: CC(CO)(C(=O)O)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To a solution of an optically active form (26.6 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid in tetrahydrofuran (40 ml) was added dropwise at room temperature a 1.09M solution (200 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture was added dropwise ethanol (25 ml) at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) and the mixture was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (17.4 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]=1[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29].[O:30]1[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31]1>C1COCC1.CCCCCC>[O:30]1[CH:34]=[CH:33][C:32]([CH:35]([OH:36])[CH:18]2[C:17](=[O:20])[C:16]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])=[C:15]([O:14][CH3:13])[CH2:19]2)=[CH:31]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Reactant: O=Cc1ccoc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)c2ccoc2)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.1 %

Procedure:
To a solution of diisopropylamine (527 μl) in THF (5 ml) under nitrogen at −78° C. is added, dropwise, butyl lithium, 2.5M solution in hexane (1.32 ml) and the reaction allowed to stir at −78° C. for 20 minutes. This solution is then added dropwise to a solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (691 mg) in THF (5 ml) under nitrogen at −78° C. and the resulting solution allowed to stir for a further 30 minutes. A solution of 3-furaldehyde (377 mg) in THF (1 ml) is then added in one portion and the reaction is allowed to warm to room temperature and stirred for a further 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (50 ml) and extracted with ethyl acetate (50 ml). The organic layer is removed and purified by automated flash chromatography to give 5-(furan-3-yl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (784 mg)
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Br:35][CH:36]([CH3:40])[C:37](Br)=[O:38].CCN(CC)CC.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:31][C:37](=[O:38])[CH:36]([Br:35])[CH3:40])=[CH:26][CH:27]=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Br)C(=O)Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)C(C)Br)c1
Yield: 66.9 %

Procedure:
Following the procedure described for Example 234, step a, reaction of {[4-(6′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (65 mg, 0.126 mmol, as prepared in Example 25, step c), racemic 2-bromo-propionyl bromide (19 μL, 0.189 mmol), and Et3N (52 μL, 0.378 mmol) in DCM (2 mL) afforded 55 mg (67%) of the title compound as a glassy solid after chromatography (PTLC, 10% EtOAc in DCM, 2×1500μ SiO2 plate). ESI-MS (m/z): Calcd. for C27H30BrN3O5S3: 652.0 (M+H); found: 653.6, 651.7, 553.9, 552.0 (M−Boc).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 48.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) and acetic anhydride (0.52 mL, 5.5 mmol) in pyridine (14 mL) provided N-(6,7,8,9-Tetrahydro-dibenzofuran-2-yl)-acetamide (0.56 g). Mp 195.5-197.5° C.; MS m/z 230 ([M+H]+); Anal. Calcd. for C15H17NO2: C, 73.34; H, 6.59; N, 6.11; Found: C, 73.45; H, 6.54; N, 6.06.