Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([Cl:17])=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(N)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (795 mg, 3.51 mmol) produced in Example D17(i) in N,N-dimethylformamide (15 mL) was added 1-chloropyrrolidine-2,5-dione (493 mg, 3.69 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 15 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (727 mg, 79%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:40][NH:41][CH3:42].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[N:41]([CH3:42])[CH3:40])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 77 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), dimethylamine hydrochloride (44 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-dimethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (120 mg, yield 77%) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([NH2:22])([CH2:16]4)[CH2:14]3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[C:39]#[N:40])=[O:33]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:21][CH:17]4[CH2:16][C:15]([NH:22][CH2:31][C:32]([N:34]5[CH2:38][CH2:37][CH2:36][C@H:35]5[C:39]#[N:40])=[O:33])([CH2:14]2)[CH:19]([CH2:18]4)[CH2:20]3)=[CH:11][CH:12]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a stirred mixture of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine (0.4 g, 1.2 mmol) and K2CO3 (0.48 g, 3.6 mmol) in DMSO (4.8 mL) at ice bath temperature was added (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.25 g, 1.44 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.28 g) in 50% yield. M.R, 214-216° C. m/z (M+1) 469; IR cm−1 3436, 2932, 2240, 1658, 1517, 1414, 1308, 1137, 952, 740. 1H NMR (300 MHz, CD3OD) δ: 7.35 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.85 (t, J=5.4 Hz, 1H), 4.15-3.95 (m, 2H), 3.81-3.70 (m, 3H), 3.60-3.50 (m, 1H), 3.42 (t, J=7.4 Hz, 2H), 2.65-2.45 (m, 4H), 2.40-1.75 (m, 14H).
Reaction SMILES: [H-].[Na+].C([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)(=O)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]1([CH2:29][C:30]([C:44]([F:47])([F:46])[F:45])([OH:43])[CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][CH2:27]1.[OH-].[Na+]>CCCCCC.C(OCC)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]1([CH2:29][C:30]([C:44]([F:47])([F:45])[F:46])([OH:43])[CH:31]([NH:6][C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)[NH:6][C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)[CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(CC2(c3cc(F)ccc3F)CC2)C(F)(F)F)cc1
Reactant: CC(=O)Nc1cccc2nc(C)ccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(NC(Nc3cccc4nc(C)ccc34)C(O)(CC3(c4cc(F)ccc4F)CC3)C(F)(F)F)cccc2n1
Yield: 18.4 %

Procedure:
Analogously to Example 76, 60 mg (1.46 mmol) of NaH (60%) and 244 mg (1.23 mmol) of 5-acetylamino-2-methyl-quinoline are reacted with 365 mg (0.81 mmol) of toluene-4-sulfonic acid-3-[1-(2,5-difluorophenyl)-cycloprop-1-yl]-2-(trifluoromethyl)-2-hydroxy-propyl ester. The crude product is treated analogously to Example 76 with 1 M sodium hydroxide solution. After chromatography on silica gel with hexane-ethyl acetate (30-50%), 67 mg of product is obtained.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:16]([N:17]=[C:5]=[O:11])[C:15]=1[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(N)cccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1N=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 229 %

Procedure:
A solution of triphosgene (2.25 g, 7.58 mmol) in toluene (27 mL), cooled in an ice-water bath, was treated slowly with a solution of 3-bromo-2-methylaniline (3.00 g, 16.1 mmol) and DIEA (5.6 mL, 32.2 mmol) in toluene (5.4 mL). The resulting suspension was stirred at room temperature for 2 h. The precipitate was removed by filtration and washed with EtOAc. The combined filtrates were diluted with EtOAc, washed with brine, dried and concentrated to provide 1-bromo-3-isocyanato-2-methylbenzene as a brown oil (3.68 g, 98% yield), used without purification. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.31 (dd, J=7.9, 0.7 Hz, 1H), 7.15 (td, J=8.0, 0.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[ClH:11].[NH3:12]>CO.C(O)C>[ClH:11].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]([NH2:12])=[NH:6]
Reactant: N
Reactant: N#Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N=C(N)c1ccc(F)c(F)c1

Procedure:
3,4-difluorobenzonitrile (4) is reacted with dried HCl gas in anhydrous methanol, followed by reacting the resulting crystals with dried ammonia gas in anhydrous ethanol to obtain 3,4-difluorobenzamidine hydrochloride (5).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[C:13]([O:21]C)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>CO>[CH3:19][O:18][C:16](/[C:15](=[CH:8]/[C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH3:4])[CH:6]=1)/[CH2:14][C:13]([OH:21])=[O:20])=[O:17]
Reactant: COC(=O)CCC(=O)OC
Reactant: Cc1cccc(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C/c1cccc(C)c1)CC(=O)O

Procedure:
To a solution of sodium methoxide (1.4 g) in methanol (20 ml}was added a mixture of 3-methylbenzaldehyde (2.4 g) and dimethyl succinate (3.5 g) and the mixture was refluxed for 3 hours. After the reaction mixture was concentrated in vacuo, water was added to the resulting residue and the mixture was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure to give 3.8 g of
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C(C)=CC=CC=1.Cl>[CH3:10][CH:9]([NH:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1)[CH3:11]
Reactant: CC(C)Nc1nccnc1Cl
Reactant: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1nccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-(1-methylethylamino)pyrazine (PREPARATION 24, 1.6 g) and piperazine (4.3 g) in xylene (10 ml) is refluxed for 26 hr. The mixture is cooled to 0° and diluted with concentrated hydrochloric acid (8 ml). The xylene is decanted and ether is added and also decanted from the salts. The salts are diluted with excess aqueous sodium hydroxide (5%) and dichloromethane. The phases are separated. The aqueous phase is extracted three more times with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated to give a liquid mixture which is flash chromatographed on silica gel eluting with methanol/chloroform (5/95). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.27, 1.83, 3.04, 4.12, 4.78, 7.49 and 7.72 δ.
Reaction SMILES: [I-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH2:19][O:20][CH3:21])[C:10](N2C=C[N+](C)=C2)=[O:11])=[CH:5][CH:4]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:18][CH2:19][O:20][CH3:21])[C:10]([N:31]2[CH2:32][CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:30]2[C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:40])[F:41])=[CH:29][CH:28]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COCCN(C(=O)n1cc[n+](C)c1)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 28 h

Procedure:
To a 50 mL round-bottomed flask was added 1-((4-fluorophenyl)(2-methoxy-ethyl)carbamoyl)-3-methyl-1H-imidazol-3-ium iodide (70 mg, 173 μmol, from step 3), (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (24 mg, 87 μmol), CH2Cl2 (1 mL), triethylamine (12 μL, 87 μmol). The reaction mixture was stirred at 40° C. for 28 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give (R)—N-(4-fluorophenyl)-N-(2-methoxyethyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 473 (M+1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1.[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:33](Cl)=[O:34])[C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1>O>[CH2:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:33]([C:27]1[C:28]2[C:29](=[O:32])[C:30]3[C:21](=[CH:20][CH:19]=[C:18]([CH3:17])[CH:31]=3)[S:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)=[O:34])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Reactant: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2sc3cccc(C(=O)N(CC(C)C)CC(C)C)c3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
1.0 g (7.75 mmoles) of diisobutyl amine is dropped into a toluene solution of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride (0.22 g, 0.78 mmoles). After 2 hours at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed with water. A crude oil is obtained after evaporation of the solvent. 11.5 mg of a yellow solid are isolated by flash chromatography of the crude oil (SiO2— eluent: CH2Cl2:MeOH 96:4).
Reaction SMILES: C1C=CC(/C=N\O)=CC=1.[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+].[I:16][C:17]1[CH:22]=C([N+]([O-])=O)[CH:20]=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1>CN(C=O)C.CCOC(C)=O>[I:16][C:17]1[CH:22]=[C:10]([OH:13])[CH:20]=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(I)cc([N+](=O)[O-])c1
Agent: O/N=C\c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(O)cc(I)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 54.8 %

Procedure:
To a solution of syn-benzaldehyde oxime (3.71 g, 30.6 mmol) in DMF (80 mL) was added cesium carbonate (19.9 g, 61.3 mmol) and heated to 90° C. for 1-2 min before a solution of 1-iodo-3-methanesulfonyl-5-nitro-benzene (5.0 g, 15.3 mmol) in DMF (80 mL) was added. The resulting dark brown solution was stirred at 90° C. for 15 h. The reaction mixture was then cooled down and diluted with EtOAc and washed with 10% HCl. The organic phase was then washed again with brine. The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to obtain a crude brown oil which was purified on ISCO column (330 g). The desired compound was eluted with 70% EtOAc-Hexanes. The desired fractions were combined and evaporated under reduced pressure to afford 2.5 g (55%) of 3-iodo-5-methanesulfonyl-phenol as an orange solid. HR-ES(+) m/e calcd for C7H7O3SI (M+H)+ 298.9234, found 298.9234.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH:6][C:23](=[O:24])[CH:21]([CH3:22])[NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-methionine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of diastereomers. The reaction was monitored by tlc (Rf=0.35 in 43% EtOAc/hexanes) and purification of this compound was by flash chromatography with 43% EtOAc/hexanes.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[S:22][C:21]([CH2:23][NH:16][CH2:15][CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[F:2])=[CH:20][CH:19]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Reactant: O=Cc1ccc(Cl)s1
Agent: [Cl-]
Product: Fc1c(OCCNCc2ccc(Cl)s2)ccc2ccccc12
Yield: 71 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 5-chlorothiophen-2-carbaldehyde in 71% yield as a slightly white oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)(=[O:24])=[O:23]
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
10 g of (R)-1-(phenylmethyl)-3-pyrrolidinol were dissolved in 160 ml of anhydrous toluene. The solution was stirred under a stream of nitrogen, cooled in an ice/ethanol bath and 8.7 ml of triethylamine were added. At a temperature of −5° C. 4,9 ml of a solution of methanesulfonylchloride in 110 ml of anhydrous toluene were added dropwise over 1,5 hours and the reaction mixture was stirred for 1 hour at 0° C. The solid was filtered and washed with ethyl acetate. The filtrate was washed with water, dried and evaporated in vacuo to give 13,9 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine as an almost colourless oil. M.S. (C.I.) (M/Z): 256 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)cs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Yield: 99.5 %

Procedure:
A solution of methyl 4-bromo-2-thiophenecarboxylate (2.5 g, 11.31 mmol), potassium carbonate (7.81 g, 56.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.565 mmol) in 1,4-dioxane (47.1 ml) and water (9.42 ml) was stirred at 80° C. in a sealed tube for 1 h. The mixture was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol, 99% yield) as a yellow solid:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(NC(C)C)(C)C.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>ClCCl>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: OCCc1cccs1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCCOCOCCc1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
15.0 g of 2-thiopheneethanol was dissolved in 350 mL of dichloromethane, and 30.2 g of diisopropylamine was added thereto. The resulting mixture was cooled to 0° C. and 17.5 g of 2-methoxyethoxymethyl chloride was added thereto. The resulting mixture was stirred for 2 hours and heated to reflux for 2 hours. The reaction product solution was cooled and concentrated by evaporation under reduced pressure. To the residue, 200 mL of water and 250 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 700 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.5 g (yield of 85%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].ClC(Cl)(Cl)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([O:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH3:15])[CH3:12]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: C=COCC
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(C)Oc1ccc2c(c1)OCO2
Yield: 98 %

Procedure:
A stirred solution of 3,4-methylenedioxyphenol (6.0 g, 43.5 mmol), ethyl vinyl ether (3.75 g, 52.0 mmol) and a catalytic amount of trichloroacetic acid (50 mg, 0.3 mmol) in chloroform (50 ml) was stirred for two hours at room temperature. Aqueous NaOH (2N, 50 ml) was added and the resulting mixture was extracted with diethyl ether (3 times). The combined ether extracts were washed with aqueous NaOH (2N) and water, respectively, dried over Na2SO4, filtered and evaporated in vacuo to yield 5-(1-ethoxyethoxy)-1,3-benzodioxole (8.96 g, 98% yield; compound No. 1) as an oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22](O)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1.Cl.[F:28][CH:29]1[CH2:32][NH:31][CH2:30]1>>[F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([N:31]3[CH2:32][CH:29]([F:28])[CH2:30]3)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: FC1CNC1
Reactant: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: Cl
Product: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Yield: 84.7 %

Procedure:
The product was prepared in the same manner as described in example 70f using 5-(2-((2-fluoroethyl)(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 277 μmol) and 3-fluoroazetidine hydrochloride (92.6 mg, 830 μmol) as starting materials. The reaction affords 4-(3-fluoro-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid {2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide (98.2 mg, 84.8%) as white solid. mp: 233-236° C., MS: m/z=419.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[NH:7][C:6]1=[O:16].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[N:7]([CH3:22])[C:6]1=[O:16]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1Nc1cccc(Cl)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Nc2cccc(Cl)c2Cl)c1=O
Temperature: 25 °C

Procedure:
52.5 g (0.154 mol) of 3-(2,3-dichloroanilino)-6-trifluoromethyluracil and 42.67 g (0.309 mol) of potassium carbonate are introduced into 700 ml of acetone. 27.74 g (0.22 mol) of dimethyl sulfate are added, with stirring, at room temperature. The mixture is subsequently refluxed for one hour. After cooling, the solids are filtered off with suction, and the filtrate is concentrated in vacuo. The pale brown crystalline residue is stirred with 500 ml of diisopropyl ether and filtered off with suction. This gives 49.5 g (91% of theory) of 3-(2,3-dichloroanilino)-1-methyl-6-trifluoromethyluracil with a melting point of 179° C. and a retention value of 0.49 (silica gel, hexane/ethyl acetate 1:1).