Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([NH:18][C:19]([NH2:21])=[NH:20])#[N:17]>>[NH2:21][C:19]1[N:18]=[C:16]([NH2:17])[C:13]2[CH2:14][CH:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:11][C:12]=2[N:20]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(C#Cc2ccccc2)CC1
Product: Nc1nc(N)c2c(n1)CCC(C#Cc1ccccc1)C2

Procedure:
When n is the bridging group --C(Cl)=CH--, 1,4-cyclohexanedione mono-ethylene ketal is reduced with sodium borohydride in ethanol, yielding the corresponding 1,4-dioxaspiro[4.5]decan-8-ol. The so-prepared alcohol is then treated with methanesulfonyl chloride under basic conditions in methylene chloride, affording 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane, which is in turn treated with sodium hydride in tetrahydrofuran, and then is reacted with trimethylsilylacetylene, yielding 8-(trimethylsilylethynyl)-1,4-dioxaspiro[4.5]decane. This compound is then treated with sodium carbonate in methanol to unprotect the ethynyl moiety, affording 8-ethynyl-1,4-dioxaspiro[4.5]decane. The so-prepared ethynyl compound is reacted with an appropriately substituted or unsubstituted phenyl iodide, for example, 3,5-di(trifluoromethyl)phenyl iodide, under basic conditions in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in acetonitrile, and then is treated with 1N hydrochloric acid, yielding the corresponding 4-(phenylethynyl)cyclohexanone. The cyclohexanone is then reacted with cyanoguanidine, as previously described, affording the 2,4-diamino-6-phenylethynyl-5,6,7,8-tetrahydroquinazoline. Chlorination of the 6-phenylethynyl-5,6,7,8-tetrahydroquinazoline, using the methods of J. Cousseau (JCS Faraday II, 1973, 1821, and JCS Perkin I, 1977, 1797), affords the targeted 2,4-diamino-6-[1-chloro-2-phenylethenyl]-5,6,7,8-tetrahydroquinazoline. Example 8 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CN1CCOCC1>C(Cl)Cl>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:26]([O:27][CH3:28])[CH3:25])=[O:17])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-cyclohexyloxy-phenyl)-acetic acid (181 mmol, 42.4 g) in anhydrous DCM (200 mL) at 0° C. was added oxalyl chloride (362 mmol, 36.6 mL) and continued stirring for 12 h during which time the reaction mixture slowly attained room temperature. The reaction mixture was concentrated in vacuo to remove volatile impurities and dried under high vacuum. To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (226 mmol, 22.1 g) and N-methylmorpholine (407 mmol, 44.8 mL) in anhydrous DCM (200 mL) at 0° C. was added the acid chloride obtained above, dissolved in DCM (50 mL) dropwise. The reaction mixture was stirred for 12 h allowing it to slowly attain room temperature. The reaction mixture was washed with water (2×200 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge with 20-30% ethyl acetate in hexanes to provide 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:42](O)=[O:43])[CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:42]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:41][CH2:40]4)=[O:43])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (88 mg) was dissolved in N,N-dimethylformamide (2.5 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (101 mg), triethylamine (0.0633 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (201 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of heptane to the resultant residue. The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (39.8 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1C
Yield: 45.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([OH:14])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:14][C:10]2[CH:11]=[C:12]([CH3:13])[C:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[NH:8][C:7]=3[CH:9]=2)[CH:21]=1
Reactant: COCc1nc2c(C)cc(O)cc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
0.77 g (4.00 mmol) 2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazol-6-ol and 0.68 g (4.40 mmol) 4,6-dichloropyrimidine in 5.0 mL DMF were combined with 1.66 g (12.0 mmol) potassium carbonate and stirred for 8 h at 70° C. Then ice water was added and the substance was extracted with ethyl acetate and concentrated by rotary evaporation i.vac. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Cl:19][C:20]1[CH:37]=[CH:36][C:23]2[NH:24][C:25]([C:27]3[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:37]=[CH:36][C:23]2[NH:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([N:1]4[CH2:5][CH2:4][CH2:3][CH:2]4[CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[O:32])=[CH:34][CH:35]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1)N1CCCC1CN1CCCC1

Procedure:
To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (11.0 mmol) and n-methylmorpholine (1.0 mmol) in dichloromethane (0.10M), slowly add the product from 4-(5-Chloro-1H-benzoimidazol-2-yl)-benzoyl chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for two hours. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane. Concentrate the organics in vacuo. Purify via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 409.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: NC1CCOCC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nc2c(c(NC3CCOCC3)n1)SCC2
Temperature: 130 °C

Procedure:
0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine followed by 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130° C. until there is no further reaction and after cooling evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH:10]([CH3:18])[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH:10]([C:11](=[O:12])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH3:18])[CH:7]=1
Reactant: CC(Br)C(=O)c1cccs1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cccs1)n1cc(Cl)cnc1=O
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-(2-bromopropionyl)thiophene (965 mg) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 3 h. the mixture was heated to 50° C. After a further 1 h. the solvent was removed and the residue dissolved in ethyl acetate (50 ml) which was washed with water (3×25 ml) and brine, dried (MgSO4) and evaporated to a yellow oil. The oil was triturated with diethyl ether and the resulting solid was crystallised twice from ethyl acetate to give the title pyrimidinone (320 mg), m.p. 128°-129° C., λmax (EtOH) 226 nm (ε 11,340), 263 nm (ε10,050), 290 nm (ε 8,950).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:12]
Reactant: Cc1c(Cl)cccc1CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(Cl)cccc1CCCBr
Yield: 90.9 %

Procedure:
Compound 54-2 (2.10 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.30 g) and N-bromosuccinimide (2.23 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.56 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[C:15]([I:21])[C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:22])[C:11]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:7][CH:6]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:11]1[C:12](=[O:22])[O:13][C:14]2[C:19]([C:10]=1[CH2:9][C:8]1[CH:31]=[CH:32][C:5]([O:4][CH2:3][CH2:2][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:6][CH:7]=1)=[CH:18][CH:17]=[C:16]([OH:20])[C:15]=2[I:21]
Reactant: C1CCNC1
Reactant: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Yield: 100 %

Procedure:
To a stirred suspension 4-(4-(2-Bromoethoxy)-benzyl)-3-(2,4-dichlorophenyl)-7-hydroxy-8-iodo-chromen-2-one (1.90 g, 2.94 mmol) in anhydrous THF (20 mL) was added pyrrolidine (1.46 mL, 17.6 mmol), and the resulting yellow solution was heated at 85° C. for 1.5 h. The resultant mixture was cooled to room temperature and the solvent was removed in vacuo. The resultant residue was dissolved in CH2Cl2, washed with H2O and brine and dried (MgSO4). The organic phase was concentrated in vacuo. The resultant residue was purified using flash chromatography (200 g silica gel, 12:1→9:1→85:15 CH2Cl2:MeOH) to afford the title compound as a yellow solid (1.87 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.26 (dd, J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.95–6.86 (m, 3H), 6.77–6.70 (m, 2H), 4.30 (t, J=5.0 Hz, 2H), 4.00 (d, J=15.5 Hz, 1H), 3.76 (d, J=15.5 Hz, 1H), 3.25 (t, J=5.0 Hz, 2H), 3.19–3.04 (m, 4H), 2.04–1.91 (m, 4H); MS (ESI) m/z 635.6 (M)+; HPLC tR 5.85 min.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(OC(C)(C)C)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Br:22][C:10]1[C:11]2[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH2:20][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:12]=2)[NH:8][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Reactant: C1COCCN1
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc2c(Br)c(-c3ccccc3)[nH]c12

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole prepared in Step B of Preparation 47 and morpholine were reacted according to the same procedures as Steps C and D of Preparation 47 to give the title compound.
Reaction SMILES: O.[F-].[K+].[Si]([C:8]([F:11])([F:10])[F:9])(C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([CH2:22][CH3:23])[C:20]#[CH:21])=[CH:15][CH:14]=1>CN(C=O)C.[Cu]I>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([C:22]#[C:23][C:8]([F:11])([F:10])[F:9])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C#CC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three-neck round-bottom flask was charged with CuI (38 mg, 0.2 mmol), Phen.H2O (40 mg, 0.2 mmol), KF (58 mg, 1.0 mmol) and stirring bar. The flask was dried at 130° C. in vacuo for 3 h. After cooling to RT, the flask was backfilled with air and TMSCF3 (142 mg, 1.0 mmol), DMF (2 mL) was added. Then the flask was heated to 130° C. for 30 min. A solution of N-(1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (102 mg, 0.2 mmol, enantiomer A) in DMF (1 mL) was slowly added to the mixture at 130° C. over 1 h. The resulting mixture was stirred for another 1 h at 130° C. The crude product was purified by Combiflash (mobile phase: CH3CN/water (0.08% of NH4HCO3)) to give the title compound. LC/MS m/z=606.7 [M+Na]
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:17]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:1]1=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCCCCO1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C1OCCCCC1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 1 mmol of caprolactone in 0.5 mL THF was added to a solution of LDA in 0.5 mL THF at -78° C. and this stirred for 2 h. Then a solution of 1.1 mmol of a benzylbromide in 0.14 mL DMPU was added to the above mixture and after stirring for 1 h at -15° C., the 2-benzylcaprolactone was isolated by extraction and chromatography.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([F:22])([F:21])[C@H:6]([OH:20])[C@H:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.[OH-].[Na+].C(O)(=O)C(C(C(O)=O)O)O>CO.O>[C:9]([NH:8][C@H:7]([C@H:6]([C:5]([F:21])([F:22])[C:4](=[O:3])[OH:23])[OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CCOC(=O)C(F)(F)[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C(F)(F)C(=O)O

Procedure:
1 g N--BOC--(4S,3R)-2,2-difluorostatine ethyl ester is dissolved in methanol/water and reacted with 0.25 g of concentrated aqueous sodium hydroxide. After 2 hours the mixture is made acidic with 2N tartaric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. N--BOC--(4S,3R)-2,2-difluorostatine is obtained (crude).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N1CCNCC1>C(Cl)Cl.CO>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Agent: C1CNCCN1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1

Procedure:
4-Chloro-7-nitroquinoline (Ellis, J.; Gellert, E.; Robson, J. Aust. J. Chem. 1973, 26, 907) (1.8 g, 8.7 mmol) and 1-tert-butoxycarbonylpiperazine (5.0 g, 27 mmol) are reacted according to method A furnishing 0.36 g of the piperazine as brown oil after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=N[CH2:40][CH2:41][CH2:42][N:43](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>CN(C)C=O.O>[CH:42]1([NH:43][C:22]([C:21]2[CH:20]=[C:19]([S:16]([N:14]3[C:13]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:12][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15]3)(=[O:18])=[O:17])[CH:27]=[CH:26][CH:25]=2)=[O:24])[CH2:40][CH2:41]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution (5 mL) of 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (150 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (92 mg), 1-hydroxy-1H-benzotriazole (73 mg) and cyclopropylamine (27 mg) at room temperature. After stirring at the same temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorless amorphous (yield 162 mg, quantitative).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[CH:14]=[O:15]>ClC1C=CC=CC=1Cl>[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[C:14]([Cl:4])=[O:15]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Reaction time: 2 h
Yield: 72 %

Procedure:
Simultaneously, 68 g of sulphuryl chloride and 70.5 g of a 2.5% solution of 2,2-azoisobutyronitrile (AIBN) are added dropwise at 80° C. to 300 g of a 22.7% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene within 4 hours. After the metered addition has ended, the reaction solution is stirred for a further 2 hours. After removal of the solvent, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 72%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCC5)c(C)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example M111) (0.33 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (223 mg, 87%).