Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH3:58])[C:52](O)=[O:53])(=[O:50])[CH3:49]>>[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH3:58])[C:52]([NH:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:53])(=[O:50])[CH3:49]
Reactant: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Reactant: CCCCC(C(C)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The amount of 2-acetylhexanoic acid in dichloromethane from Example 15A is treated with 2.3 g (17.0 mmol) of 1-hydroxy-1H-benzotriazole and 3.44 g (34 mmol) of 4-methylmorpholine and cooled to −20° C. After addition of 3.26 g (17.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, the mixture is stirred for 30 min. The cooling bath is removed in the course of this. 1.60 g (6.55 mmol) of 6-(1-aminoethyl)-3-(4-methylbenzyl)-1,2,4-triazin-5(4H)-one (Example 8A) are then added after fresh cooling to −20° C. and the mixture is stirred overnight while warming to room temperature. For work-up, the dichloromethane phase is washed with 1 N potassium hydrogensulphate solution and then with saturated sodium hydrogencarbonate solution. The dried organic phase is concentrated and chromatographed using the eluent dichloromethane/methanol 100/1 to 30/1.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:42])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:41])(C)(C)C>ClCCl>[CH3:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH2:15][CH2:14][C:13]([OH:42])=[O:12]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid tert-butyl ester from Example E76.1 (80 mg, 0.17 mmol) in dichloromethane (10 ml). The mixture was stirred for 2 h at room temperature, concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (71 mg, 100%).
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.S(=O)(=O)(O)O.[H][H]>[Pt]=O.C(O)(=O)C>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: [H][H]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: O=[Pt]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
8.4 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)imino]imidazolidine in 30 ml. of glacial acetic acid and 2.5 ml. of concentrated sulfuric acid are hydrogenated under normal pressure in the presence of 300 mg. of platinum oxide. After the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and the solution is rendered alkaline with sodium carbonate. The precipitate which has formed is filtered off, washed with a little water and dried in vacuo, whereupon 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine, m.p. 215°-216°, is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1(OS(C)(=O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CS(=O)(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(I)ccc1OC1CCCCC1

Procedure:
In a manner similar to the methods described in Example 128a and 112b, 5-iodo-2-hydroxy-benzaldehyde was reacted with methanesulfonic acid cyclohexyl ester and potassium carbonate to give 5-Iodo-2-(cyclohexyloxy)-benzaldehyde, which was subsequently reacted with LHMDS, acetyl chloride, triethylamine and chloro-trimethyl-silane to give the title compound and directly used for the next step.
Reaction SMILES: C(OC([N:6]=[S@@:7]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C@@H:26]([CH2:29][OH:30])[CH2:27][CH3:28])[C:22]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][N:20]=2)=[CH:14][CH:13]=1)([CH:9]1[CH2:11][CH2:10]1)=[O:8])=O)C.CC[O-].[Na+]>>[OH:30][CH2:29][C@H:26]([NH:25][C:23]1[C:22]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[CH:21][N:20]=[C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([S@@:7]([CH:9]3[CH2:11][CH2:10]3)(=[NH:6])=[O:8])=[CH:17][CH:16]=2)[N:24]=1)[CH2:27][CH3:28]
Reactant: CCOC(=O)N=[S@@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Agent: CC[O-]
Agent: [Na+]
Product: CC[C@H](CO)Nc1nc(Nc2ccc([S@@](=N)(=O)C3CC3)cc2)ncc1-c1cccs1
Yield: 81 %

Procedure:
In the reaction of (S)—N-(ethoxycarbonyl)-S-(4-{[4-{[(R)-1-(hydroxymethyl)propyl]-amino}-5-(2-thienyl)pyrimidine-2-yl]amino}phenyl)-S-cyclopropylsulfoximide with sodium ethylate according to procedure 14, the desired product is obtained in 81% yield after chromatographic purification (silica gel, dichloromethane/ethanol (0-10% ethanol)).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[Cl:15][C:16]1[N:17]=[C:18]([CH3:23])[N:19]=[C:20]([N:1]2[CH2:4][CH:3]([C:5]3[N:9]([CH3:10])[C:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=4[N:6]=3)[CH2:2]2)[CH:21]=1
Reactant: Cn1c(C2CNC2)nc2ccccc21
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Intermediate 1 (8.2 g, 43.8 mmol), 4,6-dichloro-2-methylpyrimidine 2-1 (8.2 g, 50.4 mmol) and Cs2CO3 (21.4 g, 65.7 mmol) were suspended in DMA (100 mL) and the mixture was stirred at 50° C. for 3 h. The mixture was cooled to rt, diluted with EtOAc (200 mL), and washed sequentially with water, brine, and water (150 mL each). The combined aqueous phase was back extracted with EtOAc (2×100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to give a brownish solid. The solid was triturated with a diethyl ether/DCM mixture (95/5) and then filtered and dried under vacuum to give Intermediate 3 as a light brown solid (10.2 g, 74%). MS: m/z=314.2 (M+H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13]C(=O)OC(C)(C)C)=[O:6])#[N:2]>C(O)=O>[NH2:13][C@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)NCC#N
Solvent: O=CO
Product: N#CCNC(=O)[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
The nitrile compound of step 3 (5.82 g, 20.68 mmol) was dissolved in 69 mL (0.3M) of formic acid and stirred at room temperature for 5 h to completion. The formic acid was evaporated and the residue partitioned between ethyl acetate and 1 N sodium hydroxide, repeating the extraction three times with fresh ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to give 2.22 g of the crude (1R,2S)-2-amino-N-(cyanomethyl)cyclohexanecarboxamide.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1([NH2:8])[CH2:7][CH2:6]1.C[O-].[Na+].[N:12]#[C:13][Br:14]>CO>[BrH:14].[CH2:7]1[C:5]2([CH2:4][CH2:3][N:2]=[C:13]([NH2:12])[NH:8]2)[CH2:6]1
Reactant: N#CBr
Reactant: NCCC1(N)CC1
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC1=NCCC2(CC2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 2.65 g (10.11 mmol) of 1-(2-aminoethyl)cyclopropanamine hydrobromide in 21 ml of methanol was added 3.83 ml (21.24 mmol) of a solution of sodium methoxide in methanol (5.55 N). The mixture was stirred at room temperature for 2 h. The precipitate was filtered and the filtrate was evaporated. The crude was dissolved in 9 ml of water and 1.07 g (10.11 mmol) of cyanogen bromide was added portion wise. The resulting mixture was stirred at room temperature for 2 h and evaporated to dryness to give 2.08 g of pure compound as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1c(F)cccc1F
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(F)cccc4F)cc3)c2cc1OC
Yield: 74.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, 2,6-difluorophenyl isocyanate (104 mg) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 57 mg of the title compound (yield: 74%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][N:6]2[N:5]=1.[Cl:16][C:17]([F:28])([F:27])[CH2:18][CH:19]1[CH2:23][N:22]([CH2:24]Cl)[C:21](=[O:26])[CH2:20]1.N1CCCC1=O.S1C=NN2C=CN=C12>O1CCOCC1.[Cl-].[Cl-].[Zn+2].O>[Cl:16][C:17]([F:27])([F:28])[CH2:18][CH:19]1[CH2:23][N:22]([CH2:24][C:11]2[N:6]3[C:7]([S:8][C:4]([CH2:3][O:2][CH3:1])=[N:5]3)=[N:9][C:10]=2[C:12]([F:15])([F:13])[F:14])[C:21](=[O:26])[CH2:20]1
Reactant: COCc1nn2cc(C(F)(F)F)nc2s1
Reactant: O=C1CC(CC(F)(F)Cl)CN1CCl
Agent: O=C1CCCN1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: O
Product: COCc1nn2c(CN3CC(CC(F)(F)Cl)CC3=O)c(C(F)(F)F)nc2s1
Temperature: 85 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To a hot solution (80° C.) of ZnCl2 (0.23 g, 1.69 mmol, 10 mol %) and 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a28 (4 g, 16.96 mmol) in dioxane (200 ml) is added a solution of 4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18 in dioxane (5 ml). The reaction mixture is heated at 85° C. for 5 days, then a further 2 g of pyrrolidinone a18 is added in one portion and the reaction mixture is kept under agitation at 90° C. for 1 day. A further addition of pyrrolidinone a18 (2 g) in order to insure complete conversion of compound a28 and further heating of the reaction mixture at reflux for 3 days increased significatively the conversion of imidazo[2,1-b][1,3,4]thiadiazole a28. After cooling and hydrolysis (250 ml of water), the crude mixture is extracted by CH2Cl2 (2×250 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified over silicagel (eluent: CH2Cl2/MeOH/NH4OH 99/1/0.1) to afford 4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one 4.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:38][CH3:39])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:43]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:43])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:38][CH3:39])[CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
A mixture of 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylic acid (1.30 g), 1-hydroxybenzotriazole ammonia complex (0.58 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.73 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxamide as colorless crystals (1.29 g, yield 98%). Recrystallization from acetone-methanol gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].BrC1C=C(F)C(N)=C(F)C=1.C(O)(=[O:23])C>>[OH:23][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(=O)O
Agent: Nc1c(F)cc(Br)cc1F
Product: O=C(O)c1cccnc1O
Temperature: 130 °C

Procedure:
A mixture of 2-chloronicotinic acid (1.6 g, 10.15 mmol) and 4-bromo-2,6-difluoroaniline (3.24 g, 15.58 mmol) in acetic acid (40 ml) was heated overnight at 130° C. under nitrogen atmosphere. The mixture was cooled to room temperature to give a precipitate. The mixture was filtered, and the solid was rinsed with acetic acid to afford 2-hydroxynicotinic acid (side-product). A second solid precipitate when the filtrate was partially concentrated to give another precipitate which corresponds to N-(4-bromo-2,6-difluorophenyl)acetamide (another side-product). Finally the filtrate was concentrated to dryness and 3.14 g of the desired compound was obtained as a solid, containing some acetamide but the mixture was used to perform the next synthetic step.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([Br:26])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:42](OC)[CH2:43][NH2:44]>C(Cl)Cl>[CH2:1]([N:8]1[CH:42]=[CH:43][N:44]=[C:9]1[C:11]1[S:12][C:13]([Br:26])=[C:14]([C:24]#[N:25])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Br)sc(C(=O)NCc2ccccc2)c1-c1ccc(Cl)cc1Cl
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1c(Br)sc(-c2nccn2Cc2ccccc2)c1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 58.3 %

Procedure:
N-benzyl-5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (0.180 g, 0.386 mmol) was dissolved in DCM (2 mL) and phosphorus pentachloride (0.0884 g, 0.425 mmol) and 4.00 M of Hydrochloric acid in 1,4-dioxane (0.050 mL, 0.20 mmol) were added. The mixture was heated in a sealed vial at 60° C. for 2 hours. After cooling down to room temperature, aminoacetaldehyde dimethyl acetal (0.252 mL, 2.32 mmol) was slowly added. The mixture was heated at 60° C. for additional 1 hour. After cooling to room temperature, 4.00 M of Hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and the mixture was heated at 60° C. for 2 hours and at room temperature overnight. Solvent was concentrated and the residue was diluted with EA, washed with saturated NaHCO3, brine, dried with Na2SO4, filtered and evaporated. The residue was purified using ISCO chromatography on silica gel, elution with 10-25% EA in hexanes to give the product (0.110 g, 58%). LCMS: (FA) ES+, 488, 490, 492. 1H NMR (300 MHz, d1-chloroform) δ: 7.28 (d, J=2.07 Hz, 1H), 7.26-7.15 (m, 5H), 7.11-7.08 (d, J=8.29 Hz, 1H), 6.85 (s, 1H), 6.73-6.70 (dd, J=6.97 Hz, 1.66 Hz, 2H). 4.85-4.70 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@@H:13]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(F)cc1

Procedure:
In a manner to Example 4(a), 4-fluoro-benzene-sulfonyl chloride was condensed with (S)-2-amino-3-(1H-Indol-3-yl)-propionic acid to give the title compound, mp=57-60° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6][C:7]=1[O:8][CH2:9][CH2:10][F:11].Cl.[F:17][C:18]1([F:22])[CH2:21][NH:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][C:18]1([F:22])[CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6][C:7]=2[O:8][CH2:9][CH2:10][F:11])[CH2:19]1
Reactant: FC1(F)CNC1
Reactant: COC(=O)c1ccc(Br)c(OCCF)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Yield: 54 %

Procedure:
In analogy to the procedure described in Example 1 a), methyl 5-bromo-6-(2-fluoroethoxyl)pyridine-2-carboxylate (Example 147 a, 130 mg, 467 μmol) was reacted with 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 66.6 mg, 514 μmol) in the presence of palladium (II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and cesium carbonate to give the title compound (73 mg, 54%) as light yellow solid, MS (ESI) m/e=291.1 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1)[CH:17]=[CH2:18]>>[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[N:21]=1)[CH:17]=[CH2:18]
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: C=CCOc1cncc(Cl)n1
Product: C=CCOc1cncc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, light yellow viscous oil, MS: m/e=352.2, 354.2 (M+H+), was prepared in accordance with the general method of example 1b from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (CAS: [802905-83-5]) and 2-Allyloxy-6-chloro-pyrazine (CAS: [107466-49-9].
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNC(=O)C(C)C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and isobutyrylchloride.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[OH:9].[P:10]([Cl:14])(Cl)(Cl)=[S:11].P(Cl)(Cl)(Cl)=O>>[P:10](=[S:11])([Cl:14])([O:9][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1)[O:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1cccc(C)c1O
Reactant: S=P(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: S=P(Cl)(Oc1ccccc1)Oc1ccccc1

Procedure:
The title compound was prepared in similar fashion as compound 6, substituting phenol for 2,6-dimethylphenol and thiophosphoryl chloride for phosphorus oxychloride. The resulting oily residue was taken to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][CH3:8].[CH3:16][C:17]1([CH3:33])[O:22][C:21]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18]1=[O:32].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:33][C:17]1([CH3:16])[O:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([N:7]([CH2:6][C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=3[O:12][CH2:13][CH2:14][CH3:15])[CH3:8])=[O:31])[CH:25]=[N:26][C:20]=2[NH:19][C:18]1=[O:32]
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Reactant: CCCOc1c(CNC)cccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)C(=O)N3)cccc1OC
Reaction time: 0.08 h
Yield: 74.6 %

Procedure:
To a solution of (3-methoxy-2-propoxy-benzyl)-methyl-amine (115 mg, 0.55 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (181 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), diisopropylethylamine (261 uL, 1.5 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (110 mg, 0.55 mmol). The reaction was placed in a microwave at 130° C. for 5 min. The solution was cooled in an ice bath and water was added with rapid stirring. The precipitate was filtered, dried and triturated with diethyl ether to yield the title compound (164 mg, 75%) as a white solid and as a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.37-11.39 (m, 1H), 8.14-8.18 (m, 1H), 7.87-7.93 (m, 1H), 7.47-7.53 (m, 1H), 7.27-7.34 (m, 1H), 6.92-7.09 (m, 3H), 6.60-6.66 (m, 1H), 4.62-4.79 (m, 2H), 3.84-3.90 (m, 2H), 3.78 (s, 3H), 2.88-3.09 (m, 3H), 1.70-1.74 (m, 2H), 1.40-1.49 (m, 6H), 0.93-0.99 (m, 3H); MS (ESI) m/e 440 (C24H29N3O5+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[N:17]O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH2:17])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1c[nH]c2ccc(Br)cc12)=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C(N)Cc1c[nH]c2ccc(Br)cc12
Reaction time: 8 h
Yield: 109.6 %

Procedure:
Zinc dust (3.30 g, 50.4 mmol) was added portionwise to a stirred solution of 2-hydroxyimino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (4.10 g, 12.61 mmol) in acetic acid (100 mL) over 30 min. After stirring overnight, the mixture was filtered through CELITE® and concentrated. The residue was dissolved in 1 N HCl and re-evaporated to give 4.30 g of the title compound as a crude material. LCMS m/z (ESI) [M−HCl+H]+ calcd for C1-3H15BrN2O2 (Br79) 312.2, found 312.2.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:14][C:15]([NH:17][C:18]1[C:19]([I:29])=[C:20]([C:24]([I:28])=[CH:25][C:26]=1[I:27])[C:21]([OH:23])=[O:22])=[O:16]>CC#N>[C:21]([C:20]1[C:19]([I:29])=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:26]([I:27])=[CH:25][C:24]=1[I:28])([OH:23])=[O:22]
Reactant: C1CNCCNCCNCCN1
Reactant: O=C(CCl)Nc1c(I)cc(I)c(C(=O)O)c1I
Solvent: CC#N
Product: O=C(CN1CCNCCNCCNCC1)Nc1c(I)cc(I)c(C(=O)O)c1I
Yield: 90.5 %

Procedure:
To a solution of 143.9 g of 1,4,7,10-tetraazacyclododecane (product commercially available) (0.84 mol) in 1000 ml of CH3CN under reflux, a suspension of 50 g of compound (A) 3-[(2-chloro-1-oxoethyl)amino]-2,4,6-triiodobenzoic acid (0.084 mol) in 500 ml of CH3CN is added during 1 h. The mixture is kept under reflux for 24 h, yielding a solid precipitation. The reaction mixture is filtered and the solid is purified by chromatography on silica gel. 55 g of N-(3-carboxy-2,4,6-triiodophenyl)-1,4,7,10-tetraazacyclododecane-1-acetamide (0.076 mol) are obtained.