Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CCO
Product: COc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4.79 g (0.021 mol) of 6-chloro-2-methoxy-3-nitropyridine, 40 ml of ethanol and 3.5 ml (0.042 mol) of pyrrolidine are charged to a fully equipped round-bottomed flask. The mixture is brought to reflux for 1 hour with stirring and then the mixture is cooled to ambient temperature. The product which crystallizes is filtered off and then washed with diisopropyl ether. After drying, 4.6 g of yellow powder are obtained, Yd: 96%.
Reaction SMILES: [N:1]#[C:2][C:3]#[N:4].C#N.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH2:15])[CH:9]=1.[OH-].[Na+]>CO>[Cl:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]=[C:2]([NH2:1])[C:3]([NH2:4])=[N:15]2
Reactant: N#CC#N
Reactant: Nc1ccc(Cl)cc1N
Agent: C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2ccc(Cl)cc2nc1N
Reaction time: 48 h
Yield: 43 %

Procedure:
60 G (1.15 moles of cyanogen, which had beforehand been freed of adhering hydrocyanic acid by washing with a silver nitrate solution containing nitric acid and had been condensed in a cold trap, were passed at room temperature into a solution of 71.3 g (0.5 mole) of 1-chloro-3,4-diaminobenzene and 2 ml of 10% strength sodium hydroxide solution in 200 ml of anhydrous methanol. The reaction mixture was left to stand for 2 days at room temperature. Thereafter the resulting precipitate was filtered off, rinsed with a little methanol and dried. 41.6 G (representing 43% of theory) of 6-chloro-2,3-diamino-quinoxaline of melting point 290°C were obtained.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12].C(O)CC>ClC>[NH:11]([C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: Fc1cnc(F)c(F)c1
Reactant: NN
Agent: CCl
Solvent: CCCO
Solvent: O
Product: NNc1ncc(F)cc1F
Yield: 85.6 %

Procedure:
6.65 g of the compound obtained in Step 3 and 4.6 ml of hydrazine monohydrate were added to 100 ml of n-propanol. The resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The resulting organic layer was concentrated under a reduced pressure to obtain 6.20 g (yield: 85.6%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (350 mg, 1.38 mmol) and 1-bromooctadecane (1.15 g, 3.45 mmol), alcohol 46 was obtained as a colorless oil (395 mg, 56% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[OH:27])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (59.4 mg), 2-hydroxy-5-methoxyacetophenone (436 mg), and 4-dimethylaminopyridine (328 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 6 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (68.6 mg, yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH:18]([CH3:20])[CH3:19])[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]2)=[CH:4][CH:3]=1.[CH:21]([C:24]1[C:25]([S:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:26][C:27]2[S:31][CH:30]=[N:29][C:28]=2[CH:32]=1)([CH3:23])[CH3:22].CCN(CC)CC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2([CH:18]([CH3:20])[CH3:19])[O:15][C:14](=[O:16])[C:13]([S:33][C:25]3[C:24]([CH:21]([CH3:23])[CH3:22])=[CH:32][C:28]4[N:29]=[CH:30][S:31][C:27]=4[CH:26]=3)=[C:12]([OH:17])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc3scnc3cc2C(C)C)cc1
Reactant: CC(C)C1(CCc2ccc(F)cc2)CC(O)=CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1cc2ncsc2cc1SC1=C(O)CC(CCc2ccc(F)cc2)(C(C)C)OC1=O

Procedure:
The title compound was prepared according to General Method 16b using 6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acid S-(5-isopropyl-benzothiazol-6-yl)ester (Example BB-4; 0.65 g, 1.8 mmol), NEt3 (0.22 g, 2.16 mmol), and acetonitrile (10 mL). The crude compound was purified by flash silica gel chromatography (25% EtOAc in hexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp 104-105° C. MS (APCI): 486.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(N(CC)CC)C>ClCCl>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:7](=[O:8])[C:6]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:31][C:32]=1[C:38]([F:39])([F:40])[F:41])#[N:35]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-isopropoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C(C1C=C(C=CC=1CC)C(C1C=CC=CC=1)=O)C.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH3:28])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:38](Cl)=[O:39]>>[CH2:19]([C:21]1[CH:26]=[C:25]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:35]([O:34][CH3:33])[CH:36]=2)[CH:24]=[CH:23][C:22]=1[CH2:27][CH3:28])[CH3:20]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCc1ccccc1CC
Agent: CCc1ccc(C(=O)c2ccccc2)cc1CC
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC

Procedure:
3′,4′-Diethyl-3,4-dimethoxybenzophenone was prepared analogously to 3,4-diethylbenzophenone using diethylbenzene (2.5 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 3,4-dimethoxybenzoyl chloride (3 g, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 1.5% ethyl acetate/hexane) to afford 0.84 g (20%) of the product as an orange solid: mp 60-61° C.; 1H NMR (CDCl3) δ7.74-7.15 (m, 5 H), 7.00-6.80 (m, 1 H) 3.96 (s, 3 H), 3.94 (s, 3 H), 2.93-2.60 (m, 4 H), 1.43-1.15 (m, 6 H); 13C NMR (CDCl3) δ195.5, 152.7, 148 146.3, 141.7, 135.9, 130.6, 129.8, 128.0, 127.7, 125.1, 112.2, 109.7, 56.0, 25.6, 25.4, 15.1, 15.0; Anal. Calcd for C19H22O3. Theoretical: C, 76.48; H, 7.43. Found: C, 76.53; H, 7.34.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([Cl:21])=[CH:12][C:11]=1[O:22][CH3:23])[CH2:4]C)C.C(N(CC)CC)C.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[C:14]([N:16]([S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([Cl:21])=[CH:12][C:11]=1[O:22][CH3:23])[CH3:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCN(CC)CCNC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(N(S(C)(=O)=O)S(=O)(=O)N(C)C)cc1C(=O)NCCN(C)C

Procedure:
A solution of N-(diethylaminoethyl)-4-chloro-5-methanesulfonamido-2-methoxybenzamide (570 mg), triethylamine (914 mg) and N,N-dimethylsulfamoyl chloride (1.3 g) in methylene chloride (30 ml) is refluxed for 40 hours. The reaction mixture is mixed with aqueous sodium hydrogen-carbonate. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The intermediary N-(dimethylaminoethyl)-4-chloro-5-[N-(dimethylaminosulfonyl)-methanesulfonamido]-2-methoxybenzamide obtained as a residue is mixed with 10% aqueous sodium hydroxide (10 ml) and methanol (10 ml) and refluxed for 10 minutes. The reaction mixture is concentrated to remove methanol and the residue is once acidified with 6N hydrochloric acid, neutralized with aqueous sodium hydrogen-carbonate, salted out with brine, and shaken with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and the methylene chloride is evaporated. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride to 1% methanol/methylene chloride. The eluate is concentrated and the residue is washed with ethyl acetate-isopropyl ether to give N-(diethylaminoethyl) -4-chloro-5-(N-dimethylaminosulfonyl)amino-2-methoxybenzamide (410 mg) as crystals melting at 110° to 110.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].Cl>C(Cl)Cl.CN(C)C=O>[CH2:20]([N:22]([CH2:23][CH3:24])[C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1)=[O:11])[CH3:21]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCNCC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 120 ml of methylene chloride was suspended 6.0 g of 4-(methoxycarbonyl)-benzoic acid, to which were added 3.5 ml of oxalyl chloride and 0.05 ml of N,N-dimethylformamide at 0-5° C. After a reaction at the same temperature as above for 3 hours, the mixture was stirred at ambient temperature for 24 hours. Then, a 90.7 g portion of the reaction mixture was taken out, and 6.9 ml of diethylamine was added thereto. The mixture was stirred at ambient temperature for 3 hours, and then poured into ice water. pH was adjusted to 1.0 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 5.89 g of methyl 4-[(diethylamino)carbonyl]-benzoate was obtained as a red oily product.
Reaction SMILES: C([Li])CCC.C1C[O:9][CH2:8]C1.[F:11][C:12]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C=O)C>[F:11][C:12]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[C:16]([CH:8]=[O:9])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1
Reactant: C1CCOC1
Reactant: COCOc1cccc(-c2ccc(F)cc2)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCOc1c(C=O)ccc(-c2ccc(F)cc2)c1F
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M hexane solution, 52.2 mL) was added at −78 C to an anhydrous THF (200 mL) solution of 2,4′-difluoro-3-(methoxymethoxy)biphenyl (19.0 g) in an argon atmosphere, and then, the mixture was stirred at −78 C for 1 hour. DMF (12.9 mL) was added thereto, and then, the mixture was stirred for 3 hours in an argon atmosphere while heated from −78 C to 0 C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, then washed with saturated saline, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was solidified with hexane to obtain the title compound (16.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol; see Example 48) in dioxane (5 mL) was reacted with piperazine (9 mmol) following the general procedure H to afford 4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-yl-benzamide. The product was dissolved in dry THF (6 mL) and was treated with BOC anhydride (3.6 mmol) and stirred for 4-6 h. The solvent was removed to dryness, and the residue obtained was suspended in ether (50 mL) with stirring. The solid fondled was collected by filtration, washed with ether and dried in vacuo to afford 4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:37])([F:36])[F:35])=[O:19])=[C:13]([Cl:38])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:41]I>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:41])[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:35])([F:37])[F:36])=[O:19])=[C:13]([Cl:38])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CI
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)Cc3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1

Procedure:
In analogy to Example 1, step 2, 2-chloro-4-{3-chloro-4-[2-(2-isopropoxy-4-trifluoromethyl-quinolin-6-yl)-2-oxo-ethyl]-phenoxy}-benzonitrile was reacted with sodium hydride and methyl iodide to give the title compound as a yellow oil. MS (m/e, ISP neg. ion)=571.1 [M−H+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([CH2:11][CH:8]([C:5]2[CH:6]=[N:7][C:2]([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])=[CH:3][CH:4]=2)[C:9]#[N:10])[CH2:14][CH2:13]1
Reactant: N#CC(CC1CC1)c1ccc(Cl)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(C(C#N)CC2CC2)cn1
Temperature: 120 °C
Yield: 169.8 %

Procedure:
A solution of 2-(6-chloropyridin-3-yl)-3-cyclopropylpropanenitrile (1.0 g, 4.86 mmol), tributyl(1-ethoxyvinyl)stannane (3.4 g, 9.72 mmol), Lid (0.612 g, 14.58 mmol) and Pd(PPh3)4 (0.282 mg, 0.243 mmol) in 1,4-dioxane (20 mL) was degassed and heated to 120° C. under N2 overnight. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g), which was used for the next step without further purification.
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].CSCl.[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH:17]=[C:16]([CH3:30])[CH2:15]1.N>ClCCl>[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[C:25]([S:8][CH3:9])[NH:24]4)[CH:17]=[C:16]([CH3:30])[CH2:15]1
Reactant: CSSC
Reactant: CC1=C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: CSCl
Agent: N
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CSc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C=C(C)CN1C
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (0.74 g,) in dichloromethane (15 ml) was added dropwise over 15 minutes at -20° C. to a stirred solution of dimethyl disulphide (0.46 g), in dichloromethane (15 ml). After allowing it to reach room temperature the solution of methyl sulphenyl chloride was added dropwise to a suspension of 8,9-didehydro-6,8-dimethylergoline (2.4 g) in dichloromethane (150 ml) at -70° C. The reaction mixture was stirred and allowed to reach room temperature overnight. Cold ammonia solution was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness. Chromatography on neutral alumina (CH2Cl2) and crystallisation from cyclohexane gave the title compound, m.p. 148°-150° C. The mesylate was also prepared, m.p. 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13](NC2C=CN(C)N=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH:42]([N:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1)([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:50][C:47]2[CH:48]=[CH:49][N:45]([CH:42]([CH3:44])[CH3:43])[N:46]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 302 mg, 0.91 mmol) was suspended in methylene chloride (4.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (456 μL, 0.91 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (212 μL, 1.82 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 1-Isopropyl-1H-pyrazol-3-ylamine (114 mg, 0.91 mmol) was dissolved in methylene chloride (4.5 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-isopropyl-1H-pyrazol-3-yl)-propionamide (183 mg, 46%) as a white foam: ESI-LRMS m/e calcd for C21H28ClN3O3S [M+] 437.15, found 438.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.46 (d, J=6.6 Hz, 6H, 2×CH3), 1.44-1.94 (m, 8H, CH), 4×CH2), 2.11-2.32 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.5 Hz, 1H, CH), 4.33 (sept, J=6.6 Hz, 1H, NCH), 6.64 (d, Jo=2.3, 1H, Ar), 7.30 (d, Jo=2.3, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.86 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:27][CH:28]([CH2:31][CH3:32])[CH2:29][OH:30]>CN(C)C=O>[Br:1][C:2]1[C:3]([S:27][CH:28]([CH2:29][OH:30])[CH2:31][CH3:32])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCC(S)CO
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CO)Sc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
362 mg of (RS)-S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide is dissolved in 1.5 ml of dimethylformamide, mixed with 0.5 ml of triethylamine and 320 mg of (RS)-2-mercapto-butan-1-ol and stirred for 18 hours at room temperature. The mixture is evaporated to the dry state in a vacuum and purified by flash chromatography (dichloromethane/ethanol). 255 mg of the product with a melting point of 175-180° C. is obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([OH:20])=O)=[O:12].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38]>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38])=[O:20])=[O:12]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
3-(Indan-2-ylacetyl)-L-thioproline (11.7 g) and triethylamine (5.6 ml) were dissolved in 100 ml of methylene chloride, followed by dropwise addition of 4.95 g of pivaloyl chloride under agitation while cooling in ice for 15 minutes. Subsequently, 4.05 g of L-prolinol and 5.6 ml of triethylamine were added dropwise and stirred at room temperature for another one hour. The reaction solution were washed in 1N HCl, saturated aqueous solution of sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, followed by distillation of the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.80 g of 1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinol. Yield; 59%.