Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.Cl.[CH3:11][NH:12][O:13][CH3:14].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNOC
Reactant: CC1CC(=O)OC(=O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)CC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of 3-methylglutaric anhydride (5.0 g) and N,O-dimethylhydroxylamine hydrochloride (4.19 g) in dichloromethane (100 mL) was stirred at 0° C. and treated dropwise with pyridine (6.9 mL). The resulting solution was warmed to rt over 45 min and then stirred overnight. After this time, the mixture was concentrated under vacuum, and the resulting residue was taken up in saturated aqueous sodium chloride and 1:1 ether/dichloromethane. The aqueous and organic layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to provide 5-(methoxy(methyl)amino)-3-methyl-5-oxopentanoic acid as a yellow oil (7.27 g). Mass spectrum m/z 188.10 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7](O)[N:8]=[CH:9][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:24])=O>>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7]([Cl:24])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Oc1ncc2cc(Br)cnc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc2cc(Br)cnc2n1
Temperature: 120 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a stirred mixture of 6-bromopyrido[2,3-d]pyrimidin-2-ol (1.1 g, 4.9 mmol) in 30 mL of phosphoryl trichloride was added diisopropylethylamine (1.6 g, 12.2 mmol) at room temperature, and the reaction mixture was then stirred at 120° C. for 12 hours. Most of phosphoryl trichloride was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and added to saturated sodium bicarbonate solution (300 mL) at 0° C. The mixture was extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (800 mg, 67%) as a yellow solid. MS (ES+) C7H3BrClN3 requires: 243, 245, found: 244, 246 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]([F:23])([F:22])[F:21])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8]2[N:12]=[CH:13][C:14](I)=[CH:15][C:7]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[F:1][C:2]1[C:3]([C:20]([F:23])([F:22])[F:21])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8]2[N:12]=[CH:13][C:14]([C:34]3[CH:33]=[N:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:36][CH:35]=3)=[CH:15][C:7]1=2
Reactant: Fc1cccc(CN2CCNc3ncc(I)cc32)c1C(F)(F)F
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cccc(F)c3C(F)(F)F)CCN4)cn2)CC1
Yield: 31 %

Procedure:
1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (101 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a yellow solid (31% yield). LCMS: m/z=487.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.51 (4H, t, J=4.9 Hz), 3.49 (2H, m), 3.55 (4H, t, J=4.9 Hz), 3.63 (2H, m), 4.65 (2H, s), 5.08 (1H, bs), 6.48 (1H, d, J=1.8 Hz), 6.64 (1H, d, J=8.8 Hz), 7.09 (1H, m), 7.26 (1H, m), 7.45 (2H, m), 7.62 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=2.5 Hz).
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:22])([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:23]>O1CCCC1.O>[ClH:23].[NH2:14][C:15]([CH3:22])([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17]
Reactant: CC(C#N)(CCCF)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(C#N)CCCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.94 g (56.62 mmol; 88% purity) of rac-2-[(diphenylmethylene)amino]-5-fluoro-2-methylpentanonitrile from Example 71A were dissolved in 264.6 ml of tetrahydrofuran and 10.2 ml of water, 124.6 ml (62.28 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. The reaction solution was admixed with 28.3 ml (56.62 mmol) of hydrogen chloride solution (2 N in diethyl ether) and concentrated by rotary evaporation. The isolated crude product was reacted further directly without further purification.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:19]=4)=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.O.[OH-].[Na+]>CCO>[C:24]1([C:20]2[CH:19]=[C:18]([C:15]3[N:12]4[CH:13]=[CH:14][C:9]([C:8]5[C:3]([OH:2])=[N:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][C:11]4=[N:17][CH:16]=3)[CH:23]=[CH:22][N:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ncccc1-c1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1ncccc1-c1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1

Procedure:
7-(2-Methoxy-pyridin-3-yl)-3-(2-phenyl-pyridin-4-y1)-imidazo[1,2-a]pyridine (Ex. 1.100) (1 eq, 0.38 mmol, 145 mg) is dissolved in EtOH (0.5 ml) and HCl (37% in H2O, 0.04 eq, 0.015 mmol, 0.5 ml) is added. The reaction is heated at reflux for 3 h and is cooled down to rt before H2O is added. The pH is adjusted to 7 with the addition of NaOH (4N) and the suspension is filtered. The solid is washed with a mixture H2O/EtOH 4:1 and dried in vacuo to afford 3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-pyridin-2-ol as a light yellow oil; [M+H]+=365
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C=O.[C:11](O)(C(F)(F)F)=O>C(O)C>[CH2:11]1[NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][CH:6]=[C:5]12
Reactant: O=C(O)C(F)(F)F
Reactant: NCCn1cccc1
Agent: C=O
Solvent: CCO
Product: c1cc2n(c1)CCNC2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a ethanol solution (20 ml) of 1-(2-aminoethyl)pyrrole (9 mmol) and 37% formaldehyde (9 mmol) was added TFA (0.5 ml) and the resulting reaction mixture was stirred at 50° C. for 15 minutes. It was then cooled to come to 25° C. and stirred at this temperature for 4 hrs. Solvent was removed under reduced pressure, residue was dissolved in ethyl acetate, basified with aqueous sodium carbonate solution, organic layer was separated and dried over sodium sulfate. Evaporation of the organic layer gave the crude 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine which was dissolved in dichloromethane (90 ml) at to it DIPEA (12.15 mmol) and boc anhydride (8.9 mmol) were added at 0° C. The resulting reaction mixture was stirred for 16 hrs at 25° C. Organic layer was washed with sodium carbonate, water and brine and finally dried over sodium sulfate. Evaporation of the organic layer gave the crude product which was purified by column chromatography (1% ethyl acetate in dichloromethane). (10% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[N:5]1([CH2:11][C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][NH2:23])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH3:1][NH:2][C:3]([NH:23][NH:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:24]=[CH:25][CH:26]=[C:12]([CH2:11][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:13]=1)=[O:21])=[O:4]
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.8 ml (13 mmol) of methylisocyanate are added to 2.0 g (6.6 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]-propyl]-hydrazine carboxamide in 20 ml of THF and the reaction mixture is stirred at room temperature for one hour. The precipitate is filtered off and recrystallised from methanol. The analytical values are summarized in Table I.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[C:8](=[O:14])[C:7]1=[O:15])C.O.[NH2:18][NH2:19]>C(O)C>[CH2:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([NH:18][NH2:19])=[O:16])[C:7](=[O:15])[C:8]1=[O:14])[CH3:13]
Reactant: CCOC(=O)CN1CCN(CC)C(=O)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCN1CCN(CC(=O)NN)C(=O)C1=O
Yield: 77 %

Procedure:
As described for example 112a, (4-ethyl-2,3-dioxo-piperazin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) and the resulting mixture heated under reflux for 16 h. The precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 77%). MS: m/e=215.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([NH:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][C:26](F)=[CH:25][C:23]=3[N:24]=2)=[O:18])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NCCSC1SC=C(C(NC2N(C)[C:52]3[CH:55]=[C:56](F)[CH:57]=[CH:58][C:51]=3S2)=O)N=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([NH:19][C:20]2[S:21][C:22]3[CH:28]=[C:27]([C:51]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:52]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)=[O:18])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCSc1nc(C(=O)Nc2nc3cc(F)ccc3s2)cs1
Reactant: CN1c2cc(F)ccc2SC1NC(=O)c1csc(SCCNC(=O)OC(C)(C)C)n1
Product: CC(C)(C)OC(=O)NCCSc1nc(C(=O)Nc2nc3ccc(-c4ccccc4)cc3s2)cs1

Procedure:
In a similar manner were prepared: 2-(t-butoxy-carbonylaminoethylthio) -N-(5-fluorobenzothiazol-2-yl) -thiazole-4-carboxamide, m.p. 198-199° C. and 2-(t-butoxy-carbonylaminoethylthio)-N-(3-methyl-5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide, m.p. 204-205° C.
Reaction SMILES: [NH2:1][C@H:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>CN(C=O)C>[CH2:52]([O:51][C:49]([CH2:48][CH2:47][CH2:46][NH:1][C@H:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32])=[O:50])[CH3:53]
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 53.4 %

Procedure:
To a solution of compound 7h (2.0 g, 3.65 mmol) in DMF (8 mL) was added Na2CO3 (0.47 g, 4.38 mmol) followed by ethyl 4-bromobutyrate (0.83 mL, 5.48 mmol). The mixture was heated at 95° C. for 1.5 hours, cooled to room temperature, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate/hexanes/triethylamine 500/500/5 to afford compound 7i (1.29 g) as a white solid. MS (CI) m/z 662.2, 664.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH:26]1[CH2:25][CH:24]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanecarboxylate (0.81 g, 0.0018 mol) in dichloromethane (5 mL) was slowly added a 20% solution of trifluoroacetic acid in dichloromethane (10 mL) at 0° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature and stirred for eighteen hours. The solvent was removed under reduced pressure. An aqueous solution of 5 N sodium hydroxide was added to the residue to pH 11 at 0° C. The water phase was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.44 g, 0.0012 mol).
Reaction SMILES: [CH2:1]([N:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16][CH2:15]2)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:34]>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33]([N:18]2[C:19]3[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:22])=[CH:21][CH:20]=3)[CH2:15][CH2:16][CH2:17]2)=[O:34])=[CH:37][CH:38]=1
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To 60.4 mg (0.2 mmol) Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine in 2 ml CH2Cl2 1 drop of Huenig's base and 57 mg (0.3 mmol) 4-chlorophenyl chloroformate in 1 ml CH2Cl2 were added. The solution was stirred at RT for 30 min, was concentrated and the residue was dissolved in ether and a saturated aqueous solution of NaHCO3. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1 yielded 46 mg (50%) 6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 457 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].Cl.[F:23][C:24]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:27]3[CH2:28][CH2:29][C:24]([F:30])([F:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(F)(F)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 66.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.10 g, 0.32 mmol) in DMF (2 mL) was added 4,4-difluoropiperidine hydrochloride (0.056 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 66.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methylquinoline as a brown solid. Mass Spectrum (ESI) m/e=410.0 (M+1).
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][C:9]=1[F:19])(=[O:5])=[O:4])[CH3:2].[C:20]1([CH3:38])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=[C:28]([C:34]([F:37])([F:36])[F:35])[N:27]=2)[CH:21]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([NH:33][CH2:32][C:31]2[C:26]([C:22]3[CH:21]=[C:20]([CH3:38])[CH:25]=[CH:24][CH:23]=3)=[N:27][C:28]([C:34]([F:37])([F:35])[F:36])=[CH:29][CH:30]=2)=[O:17])=[CH:10][C:9]=1[F:19])(=[O:4])=[O:5])[CH3:2]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)cc1F
Reaction time: 8 h

Procedure:
2-(4-(Ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (61 mg, 0.228 mmol) was dissolved and mixed in 1,4-dioxane, followed by addition of N-hydroxybenzotriazole (42 mg, 0.311 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (60 mg, 0.311 mmol) and triethylamine (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 83) in pure form (52 mg, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:24]([N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl)[CH2:25][CH2:26][CH3:27]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:33][CH2:32][N:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30]1)=[O:23])[CH3:2]
Reactant: CCCCN(CCCl)CCCl
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Product: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxyic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 18.3 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:13][C:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][C:5]=1[CH3:7]
Reactant: BrBr
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c(C)c(Br)c1C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (3.42 g, 20 mmol) in carbon tetrachloride (40 mL) was added a solution of bromine in carbon tetrachloride (10 mL) dropwise at 20° C. After the addition was complete, stirring was continued for 2 h. The reaction mixture was diluted with DCM, washed with aqueous NaHCO3 and water, and then dried over Na2SO4. Evaporation of solvent gave ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate as a solid (4.8 g), which was used in the next step without purification. 1H-NMR (CDCl3): δ 9.36 (1H, s), 4.30 (2H, q), 228 (3H, s), 2.26 (3H, s), 1.36 (3H, t). To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (2.4 g, 10 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium (2.3 g, 1 mmol). After stirring 15 min, the reaction mixture was charged with 2-(trifluoromethyl)-benzeneboronic acid (2.4 g, 12.5 mmol) and sodium carbonate (in 5 mL of water). The reaction mixture was heated to reflux overnight with stirring. After cooling, the reaction mixture was then diluted with water and extracted with DCM. The combined extracts were washed with water and dried over Na2SO4. Evaporation of solvent gave a crude material, which was purified by chromatography on silica gel column eluting with EtOAc-hexane (1:1) to give the title compound (1.5 g). MS (ES): 312 (MH+);
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]1[C:23]2([CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:22]1[C:23]2([CH2:27][CH2:26][CH2:25][N:24]2[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:21]1
Reactant: C1CNC2(C1)CC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCCC12CC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4-azaspiro[2.4]heptane (95442-76-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=364.5 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([O:14][C:25]2[N:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:23]([O:22][CH3:21])[N:24]=2)[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)c1cccc(OC)c1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
8 g (230 mmol) Methyl 2-(3-methoxyphenyl)glycolate was dissolved in 100 ml dimethylformamide and treated with 2.8 g (20.4 mmol) potassium carbonate. After 20 minutes stirring, 8.8 g (40.7 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added and the mixture heated for 1 hour at 90° C. The reaction mixture was then poured into 100 ml water and extracted with 100 ml ethyl acetate. The combined ethyl acetate phase was washed with water, dried over magnesium sulphate and evaporated. The residue was recrystallised from diisopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:4][CH:3]=1.[Si]([N:23]=[N+:24]=[N-])(C)(C)C>>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:17][CH:18]=1)=[N+:23]=[N-:24]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)N[C@@H](CO)C(=O)NCc1ccc(N)cc1
Product: CC(=O)N[C@@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Yield: 92.1 %

Procedure:
Using (S)—N-(4-aminobenzyl)-2-acetamido-3-hydroxypropanamide (2.80 g, 11.16 mmol), t-BuONO (3.98 mL, 33.48 mmol), TMSN3 (3.52 mL, 26.78 mmol), and the preceding procedure gave 2.85 g (92%) of (S)—N-(4-azidobenzyl)-2-acetamido-3-hydroxypropanamide as a white solid: mp 161-162° C.; [α]26D −13.6° (c 1.0, MeOH); Rf=0.35 (1/9 MeOH/CHCl3); IR (nujol mull) 3267, 2924, 2129, 1648, 1552, 1459 cm−1; 1H NMR (DMSO-d6) δ 1.87 (s, CH3C(O)), 3.58 (t, J=5.6 Hz, CH2OH), 4.26-4.31 (m, CH2Ar and CH), 4.91 (t, J=5.6 Hz, OH), 7.03-7.08 (m, 2 ArH), 7.27-7.32 (m, 2 ArH), 7.94 (d, J=7.8 Hz, NHCH), 8.40 (t, J=6.0 Hz, NHCH2); 13C NMR (DMSO-d6) δ 22.6 (CH3C(O)), 41.5 (CH2Ph), 55.3 (CH), 61.7 (CH2OH), 118.9, 128.7, 136.5, 137.7 (C6H5), 169.4, 170.3 (2 C(O)); HRMS (ESI) 278.1248 [M+H+] (calcd. for C12H16N5O3 278.1253); Anal. (C12H15N5O3) Calcd.: C, 51.98%; H, 5.45%; N, 25.26%. Found: C, 52.08%; H, 5.51%; N, 25.00%.