Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21]>N1CCCCC1.C(O)C>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:18]2[C:11]3[C:10]([NH:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)=[N:15][CH:14]=[N:13][C:12]=3[NH:16][C:17]2=[O:19])[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (66 mg, 0.24 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (63.7 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 78.5 mg (62%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.33 (br s, 1H, NH), 11.61 (br s, 1H, NH), 9.17 (br s, 1H), 8.29 (s, 1H), 7.69 (dd, J=2.5 & 6.5 Hz, 1H), 7.35 (m, 4H), 3.29 (m, 2H, CH2), 2.5 (m, 6H, N(CH2CH3)2 & CH2), 2.45 (s, 3H, CH3), 2.25 (s, 3H, CH3), 0.96 (t, J=7 Hz, 6H, N(CH2CH3)2). MS 526 [M++1].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]1([C:19]2([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[CH3:1][S:2]([O:25][CH2:24][C:19]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:4])=[O:3]
Reactant: OCC1(c2ccccc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 1 h

Procedure:
659 mg (6.07 mmol) of methanesulfonyl chloride and then 838 μl (6.01 mmol) of triethylamine were added, whilst cooling in an ice-salt bath, to a solution of 1.00 g (5.67 mmol) of (1-phenylcyclopentyl)methanol [prepared as described in step (i) above] in 18 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted mixture was washed with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.44 g (a quantitative yield) of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[O:25][C:24]([C:26]3[N:27]=[C:28]4[N:32]([CH:33]=3)[N:31]=[C:30]([O:34][CH3:35])[S:29]4)=[CH:23][C:22]2=C(O)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(Cl)Cl.C1C=CC=CC=1>[CH3:35][O:34][C:30]1[S:29][C:28]2=[N:27][C:26]([C:24]3[O:25][C:21]4[CH:20]=[C:19]([O:18][CH3:17])[CH:16]=[C:15]([O:14][CH2:12][C:10]5[S:11][C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[N:8][N:9]=5)[C:22]=4[CH:23]=3)=[CH:33][N:32]2[N:31]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)s1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OCc2nnc(-c3ccccc3)s2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reaction time: 0.01 h
Yield: 29.1 %

Procedure:
In a 200 mL round-bottomed flask, benzene was added to ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (Example 8B, 80 mgs, 0.252 mmol) and 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 58.2 mgs, 0.303 mmol) and the mixture was sonificated for 30 sec. and concentrated in vacuo to remove traces of water in the starting material. Triphenylphosphine (99 mgs, 0.378 mmol) was added and the mixture was dried on high vacuum for 10 min. THF (40 mL) were added and the mixture was sonificated/heated for 5 min. Diisopropyl azodicarboxylate (68.6 μl, 0.353 mmol) in THF (4 mL) was added dropwise on app. 1 h and LC/MS showed that the reaction was not complete. Diisopropyl azodicarboxylate (2 drops) were added again and the mixture was diluted in CH2Cl2, washed with sat. aqueous NaHCO3 (1×), brine (1×), and dried over anhydrous MgSO4 and concentrated. The residue was purified on silica gel chromatography (100% CH2Cl2 up to 15% EtOAc/CH2Cl2) to give a residue which was triturated with MeCN and afforded the title material (36 mgs, 29%). LC (Method A): 2.901 min. HRMS (ESI) calcd for C23H17N5O4S2 [M+H]+ m/z 492.0722, found 492.0806. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.96-8.02 (m, 2H), 7.87 (s, 1H), 7.45-7.55 (m, 3H), 7.10 (s, 1H), 6.73-6.78 (m, 1H), 6.48 (d, J=1.57 Hz, 1H), 5.63 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][NH:13][C:12](=[O:20])[CH:11]=2)[CH:3]=1.Br[CH:22]([CH3:26])[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][N:13]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[C:12](=[O:20])[CH:11]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C(F)(F)F
Reactant: CC(Br)C(=O)O
Product: CC(C(=O)O)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
456 mg (purity 86%, 1.31 mmol) of 4-chloro-2-[2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-4-yl]benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 515 mg (purity 51%, 54% of theory)
Reaction SMILES: [C:1](=[C:3]1N=C2C=CC=CC2=N1)=O.[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:17])=[O:16])([CH3:14])[CH3:13].C([Mg]Br)C.CO>C(OCC)C>[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([OH:34])[CH2:1][CH3:3])[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:16])=[O:17])([CH3:14])[CH3:13]
Reactant: O=C=C1N=c2ccccc2=N1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: CC[Mg]Br
Solvent: CO
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
The 1-hydroxy-1-(C1 -C7 alkyl)benzyl derivatives, the carbinols, can also be prepared by reacting the corresponding carbonyl derivative with the appropriate Grignard reagent followed by hydrolysis. The carbonyl benzimidazole, 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, is reacted with ethylmagnesium bromide in anhydrous ethyl ether and then hydrolyzed to form the carbinol, 1-isopropylsulfonyl-2-amino-6-(1-phenyl-1-hydroxy-1-propyl)benzimidazole. The Grignard reagent, ethylmagnesium bromide, is made from ethylbromide and metallic magnesium in anhydrous ethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:29]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=4)=[O:30])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: Cn1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 40 mg, 0.13 mmol, prepared as described in a previous example), 1-methyl-1H-imidazole-2-carboxylic acid (34 mg, 0.27 mmol), and HATU (102 mg, 0.27 mmol) was added 1.0 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.07 mL, 0.4 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish solid (37 mg, 68% yield). MS (apci) m/z=406.2 (M+H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[CH2:17][CH2:18][OH:19].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=1>C(#N)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=2)[CH2:13][CH:12]1[CH2:17][CH2:18][OH:19]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1CCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(N2CCN(C)C(CCO)C2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 70.8 %

Procedure:
974 mg of N,N-diisopropylethylamine and 724 mg of 2-(1-methylpiperazin-2-yl)ethanol are added to a suspension of 1 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in 10 ml of acetonitrile. The reaction medium is microwave-heated at 110° C. for 6 hours and then concentrated to dryness under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (100/0) to (90/10). 1.15 g of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanol are obtained in the form of a yellow oil.
Reaction SMILES: ClC1C=CC(F)=C2C=1C=C(O)N=C2.CO[CH:16](OC)[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=1)=[O:18].OS(O)(=O)=O.OS(O)(=O)=O.O=S(=O)=O>>[F:29][C:28]([F:31])([F:30])[O:27][C:23]1[CH:22]=[C:21]2[C:26]([CH:16]=[C:17]([OH:18])[N:19]=[CH:20]2)=[CH:25][CH:24]=1
Reactant: COC(OC)C(=O)NCc1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: Oc1cc2c(Cl)ccc(F)c2cn1
Product: Oc1cc2ccc(OC(F)(F)F)cc2cn1

Procedure:
By following the procedure for the preparation of 5-chloro-8-fluoroisoquinolin-3-ol, the title compound was prepared from 2,2-dimethoxy-N-(3-trifluoromethoxybenzyl)-acetamide (5.0 g, 17 mmol), conc. H2SO4 (9.0 mL) and oleum (30%; 10.8 mL). 1H NMR (CDCl3, 300 MHz): δ=6.80 (s, 1H), 7.22 (d, J=6.8 Hz, 1H), 7.42 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 8.44 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:19]=[CH:18]4)[C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:31][C:32]([F:37])([CH3:36])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl>CN1C(=O)CCC1>[O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[N:19]=[CH:18]4)[C@@H:11]([NH:13][C:33](=[O:34])[C:32]([F:37])([F:31])[CH3:36])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(F)(F)C(=O)O
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of (1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (306a, 85 mg, 0.21 mmol) in NMP (1 mL) was added a solution of 2,2-difluoropropanoic acid (37 mg, 0.34 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.128 g, 340 nmol), and N-ethyl-N-isopropylpropan-2-amine (140 μL, 840 μmol) in NMP (2 mL). The mixture was stirred at r.t. for 2 h. Then aq. HCl (1N, 30 mL) was added, and the mixture was extracted with ethyl acetate (3×45 ml). The organic phase was dried and purified by flash chromatography on silica gel with ethyl acetane/n-heptane (2:1) to give 65 mg (62%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].C(N(CC)CC)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH3:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 43.8 %

Procedure:
A 500 mL 3-neck round bottom flask was charged with t-butyl carbazate (15.0 g, 113.5 mmol), toluene (120 mL), triethylamine (18.98 mL, 136.2 mmol) and ethyl bromoacetate (15.10 mL, 136.2 mmol). The mixture was heated in an oil bath to about 100° C. for 19 hours. The reaction mixture was allowed to cool to room temperature and was then filtered, washing the solid triethylamine bromide with ethyl acetate/hexanes. The combined organics were washed successively with saturated sodium bicarbonate, water and brine, dried over sodium sulfate, filtered, concentrated and dried in vacuo to give a crude reddish oil (20.78 g). The crude material was absorbed onto Celite® and purified on a 10×20 cm silica gel column eluting with 15% (4 L), 20% (7 L), 30% (2 L), 40% (2 L), 50% (2 L) ethyl acetate/hexanes and finally ethyl acetate (2 L). The desired fractions were combined and concentrated to give an oil (10.85 g) which solidified upon standing. The residue was concentrated with dichloro-methane/toluene and dried in vacuo to give compound A (44%) as an off-white solid. TLC: Rf =0.13, silica gel, 30% ethyl acetate/hexanes, UV and PMA detection.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl.[S:23]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)([O-:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[C:30]1([CH3:31])[CH:29]=[CH:28][C:27]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:33][CH:32]=1.[OH:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: COC(=O)C/C=C\CCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
p-Toluene sulfonyl chloride (1.425 g., 7.5 mm.) was added at 0°C to a solution of 1.00g. (6.95 mm.) of methyl cis 6-hydroxy-3-hexenoate in 2.37 g. of dry pyridine. The resulting mixture was stirred at 0°C for 4 hours. The crude product was poured on ice and concentrated hydrochloric acid, extracted with benzene, washed with 2N hydrochloric acid, sodium carbonate till neutral and dried over potassium carbonate. Evaporation of the solvent produced 1.425 g. (68% of theory) of crude tosylate.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:11]=2)[NH:6][C:5]=1C(O)=O.C(=O)=O.C(O)(=O)CCC(O)=O.[N:33]1[C:42]2C(=CC=CC=2)C=C[CH:34]=1>>[CH3:34][N:33]([CH2:2][CH2:3][C:4]1[C:12]2[CH:11]=[C:10]([CH2:13][N:14]3[N:15]=[CH:16][N:17]=[CH:18]3)[CH:9]=[CH:8][C:7]=2[NH:6][CH:5]=1)[CH3:42]
Reactant: O=C(O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Reactant: c1ccc2ncccc2c1
Agent: O=C(O)CCC(=O)O
Agent: O=C=O
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Temperature: 25 °C
Yield: 86 %

Procedure:
700 mg (2,2 mmoles) of 3-(2-hydroxyethyl)-5-[1,2,4-triazol-1-ylmethyl]-1H-indol-2-carboxylic acid was suspended in 7 ml of dry quinoline. 14 mg of cuprous oxide was added and the stirred suspension heated, under dry nitrogen stream, to 200° C. The reaction mixture was kept at this temperature until no more CO2 was released (15-20 min.). It was left to cool to room temperature and the reaction mixture was filtered through decalite. The filtrate was concentrated by vacuum distillation of the solvent, providing a residue which was dissolved with a succinic acid solution and washed three times with 10 ml of dichloromethane. The washed aqueous phase was cooled and adjusted to pH 12 with a 40% sodium hydroxide solution and extracted three times with 20 ml of dichloromethane. The combined organic phases were dried on anhydrous sodium sulphate and evaporated to dryness. The residue was recrystallised from heptane/isopropyl acetate to give 510 mg (86%) of rizatriptan as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.Cl[C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH2:26][CH2:25][N:24]2[CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[N:16]=[N:17][C:12]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: Cc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP4, reacting 2-methylpyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[NH2:7].[N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18])=[C:10]=[O:11]>[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[NH:7][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]=[C:10]=[O:11]
Reactant: O=C=NCCCCCC(=O)Cl
Reactant: COCCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COCCOC(=O)NC(=O)CCCCCN=C=O
Temperature: 60 °C
Reaction time: 26 h
Yield: 85.2 %

Procedure:
6.65 g (0.05 mol) of carbamic acid-β-methoxyethyl ester and 0.15 g of zinc chloride were heated to 50° C. 8.8 g (0.05 mol) of 6-isocyanato-caproyl chloride were added dropwise to the resulting melt. Nitrogen was passed through the mixture while it was heated to 60° C. for 3 hours and then to 100° C. for 26 hours. The reaction was then terminated (IR control). The mixture was cooled, taken up in 100 ml of toluene and decanted to remove insoluble constituents; the toluene was removed under vacuum. 11 g of a colorless oil was obtained, which solidified to a waxy solid. Yield: 11 g=85%
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([C:25]([CH3:35])([CH3:34])[CH2:26][C:27]2([C:30]([F:33])([F:32])[F:31])[CH2:29][O:28]2)[C:19]2[O:23][CH2:22][CH2:21][C:20]=2[CH:24]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:25]([CH3:35])([CH3:34])[CH2:26][C:27]([CH2:29][C:2]2[S:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=2)([OH:28])[C:30]([F:31])([F:32])[F:33])[C:19]2[O:23][CH2:22][CH2:21][C:20]=2[CH:24]=1
Reactant: c1cc2sccc2cn1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1cc2cnccc2s1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A solution of thieno[3,2-c]pyridine (prepared according to the procedure by J. H. Wikel, M. L. Denney, and R. T. J. Vasileff, Heterocyclic Chem. 1993, 30, pp. 289-290) (152 mg, 1.12 mmol) in 2 mL of THF was treated with 450 μL of n-BuLi (2.5 M in hexanes) in a dropwise manner at −78° C. The resulting dark reaction mixture was stirred for 30 minutes and treated with a solution of 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (180 mg, 0.561 mmol) in 0.5 mL of THF. The reaction was allowed to warm to room temperature overnight and quenched with a mixture of 5 mL of saturated ammonium chloride solution and 10 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography (ethyl acetate-hexanes, 20%-30% gradient) gave 33.5 mg (13% yield) of the title product as yellow foam.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][S:6](=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:17].[Na+].Cl.CCOC(C)=O>C(#N)C.O>[CH3:1][C@H:2]1[O:7][S:6](=[O:17])(=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 46.8 %

Procedure:
To a solution of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (2.3 g, 9.6 mmol) in acetonitrile (25 mL) and water (15 mL) cooled to 0° C. is added sodium periodate (3.1 g, 14.3 mmol) in one portion. After 5 min, the pH of the mixture is adjusted to 7-8 by addition of saturated Na2HPO4 solution. A solution of RuCl3 (9.9 mg, 0.05 mmol) in water (0.5 mL) is added and the reaction mixture is stirred for 2 h, keeping the pH between 6 and 9 by addition of Na2HPO4 solution. Water (100 mL) is added and the pH is adjusted to 6 by addition of 2M HCl solution. EtOAc is added and the organic layer is separated, washed with NaHCO3 and brine. The combined aqueous layers are back extracted once with EtOAc. The combined organic phases are dried (MgSO4) and concentrated to afford the crude compound which is purified by flash column chromatography using EtOAc in hexanes affords the title compound (1.13 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([C@H:45]1[CH2:49][NH:48][C@H:47]([C:50]([O:52][CH3:53])=[O:51])[CH2:46]1)(=[O:44])=[O:43].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:48]3[CH2:49][C@H:45]([S:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[Cl:35])(=[O:44])=[O:43])[CH2:46][C@H:47]3[C:50]([O:52][CH3:53])=[O:51])=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 1-(4-chlorophenyl)cyclopropanecarboxylic acid (1.57 g, 7.9 mmol, Eq: 1.20) was combined with tetrahydrofuran (70.0 ml) to give a colorless solution. Then EDC (3.09 g, 15.8 mmol, Eq: 2.40), HOBt (2.47 g, 15.8 mmol, Eq: 2.40) and triethylamine (6.66 g, 9.18 ml, 65.8 mmol, Eq: 10.0) was added. (A white suspension was obtained.) The reaction mixture was stirred for 15 min at room temperature. A solution of (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylate (2 g, 6.58 mmol, Eq: 1.00) in tetrahydrofuran (14.0 ml) was added dropwise. The reaction was stirred for 3 days at room temperature. The reaction mixture was poured into 75 ml HCl 1M and extracted with 2×100 ml ethyl acetate. The organic layers were washed with 75 ml satd. Na2CO3 solution and 75 ml brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (50 g column, from 0% to 100% ethyl acetate in heptane). The title compound was obtained as a light yellow solid (1.5 g, 47.2%, MS (m/e)=482.3 [M+H+]).