Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([CH2:43][C:44]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:40]3[CH2:39][CH2:38][N:37]([CH2:43][C:44]([N:46]4[CH2:47][CH2:48][CH2:49][CH2:50]4)=[O:45])[CH2:42][CH2:41]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound. LC-MS: 704.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C:17](Cl)=[O:18].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24].Cl>C1C=CC=CC=1>[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[O:6][C:5]([C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=1)=[C:14]([CH3:15])[C:13]2=[O:16])=[O:18])[CH3:24]
Reactant: CCN(CC)CCN
Reactant: Cc1c(-c2cccc(Cl)c2)oc2c(C(=O)Cl)cccc2c1=O
Agent: Cl
Solvent: c1ccccc1
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)c(C)c(-c3cccc(Cl)c3)oc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 33.3 %

Procedure:
To a solution of 3'-chloro-3-methylflavone-8-carboxylic acid chloride (prepared from 1.00 g of 3'-chloro-3-methylflavone-8-carboxylic acid and 0.46 ml of thionyl chloride) in 40 ml of benzene were added 0.33 g of N,N-diethylethylenediamine and the solution was stirred for 80 minutes at room temperature. To the reaction mixture was added aqueous HCl solution and shaken. The water layer was separated and made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residue was purified by column chromatography (adsorbent: silica gel, eluted with chloroform and chloroform containing 1% of methanol) to give 0.39 g of yellow crystals, which were recrystallized from isopropyl ether as colorless plates, m.p. 116°-117° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:7]=1[CH3:8])[CH3:2]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2ccc(OC)cc2)c1C
Yield: 64 %

Procedure:
9.3 grams 3,3-diacetyl-propionic acid-ethyl ester, 8.7 grams p-methoxy phenyl-hydrazinehydrochloride, 4.9 grams anhydrous sodium acetate and 90 milliliters ethanol were mixed and the mixture heated to boiling temperature under reflux for 2.5 hours. The reaction mixture was thereafter evaporated and ether added to the residue. The ether phase was extracted with water and the ether evaporated. The crystalline residue was recrystallized twice from a mixture of ethanol and water. 9.2 grams 3,5-dimethyl-1-(p-methoxy phenyl)-pyrazol-4-acetic acid-ethyl ester, melting at 71°-72° C. were obtained, representing a yield of 64%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([OH:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:18][CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OC/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCC=Cc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (E)-cinnamyl alcohol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:15](/[CH3:28])=[CH:16]/[C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[C:8]2[CH:7]=[C:6](/[C:15](/[CH3:28])=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)C(=O)CC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)C(=O)CC2(C)C
Yield: 70 %

Procedure:
2 g of ethyl (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-7-oxonaphth-2-yl)-1-propenyl]-benzoate are stirred with 0.7 g of potassium hydroxide in a mixture of 25 ml of ethanol and 1.5 ml of water for 3 hours at 80° C. The entire reaction mass is introduced into 100 ml of water, after which the mixture is acidified with 2 N hydrochloric acid, and the resulting precipitate is filtered off, washed with cold methanol and dried to give 1.3 g of the title compound of melting point 260°-261° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][NH:19][CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(Cc3ccccc3)c3ccccc23)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1

Procedure:
A solution of 9-benzyl-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]-indole (3.66 g, 10.1 mmol) in chloroform (50 ml) was stirred with trifluoroacetic acid (20 ml) at room temperature for 2 hours. The mixture was evaporated to dryness and the residue partitioned between chloroform and saturated potassium carbonate solution (150 ml/1:2). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (2.66 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16]C(C)(C)C)=O)[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:22](F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:22])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2F)CC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.69 g, 9.67 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (7.45 mL, 97 mmol) and stirred at RT for 2 h. The reaction was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a golden yellow oil. A solution of the crude golden yellow oil in CH2Cl2 (10 mL) was cooled to 0° C. and added acetic anhydride (4.5 mL, 48.3 mmol). The reaction was gradually allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a colorless oil. [M+1]=221.1.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(C)=O.C[O-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:11][C:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2c1CC=CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1=CCc2c(cccc2OCc2ccccc2)C1

Procedure:
A solution of 73 g. (0.5 m) of 5,8-dihydro-1-naphthol in 100 ml. DMSO is treated with 0.5 m sodium methoxide. The mixture is cooled in an ice bath and treated dropwise with 0.5 mole benzyl bromide with shaking periodically. The mixture is gradually allowed to warm up to about 45° toward the end of addition. The mixture is stirred 3 hrs. longer, then poured into 1 liter H2O and extracted into ether. Extracts are washed twice with 10% NaOH, dried, taken to dryness leaving almost a quantitative yield of crystalline 5,8-dihydro-1-naphthyl benzyl ether.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[CH2:15][C@@H:14]([C:18](O)=[O:19])[CH2:13]2)=[CH:8][CH:7]=1.CN.[CH3:28][N:29](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:28][NH:29][C:18]([C@@H:14]1[CH2:15][C:16](=[O:17])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])=[CH:7][CH:8]=2)[CH2:13]1)=[O:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cccc3F)cc2)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cccc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), the condensation of the (R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=361 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH:20]([C:22]3[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=3)O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:22]3[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ncc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 35 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol (608, 0.35 g, 0.78 mmol) in dichloromethane (15.0 mL) were added triethylsilane (2.00 mL, 12.52 mmol) and trifluoroacetic acid (1.00 mL, 13.0 mmol). The reaction was stirred at 35° C. overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (609, 0.25 g, 74%). MS (ESI) [M+H+]+=430.9.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14]C)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1>Br.CC(O)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[OH:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(O)c(F)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
A solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 100° C. for 1 day. The reaction mixture was cooled to 0° C. and diluted with water (400 ml). The resulting crystals were collected by filtration, affording, after drying, 12.4 g of a colourless material.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:4]=1.CO[CH:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:20]=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=3)[C:24](=[O:32])[NH:23][C:22]2=[O:33])[CH:8]=1
Reactant: NCc1cc(O)c(OCCN2CCCC2)cn1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1cc(O)c(OCCN2CCCC2)cn1

Procedure:
A mixture of 2-aminomethyl-5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ol (237 mg, 1.0 mmole), 3 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (329 mg, 1.0 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in methanol and purified by HPLC (acetonitrile/water without trifluoroacetic acid); the fractions belonging to the product peak (as determined by MS) were evaporated and still had impurities. This is re-purified by HPLC (acetonitrile water with 0.2% trifluoroacetic acid). The product is isolated by evaporation in-vacuo to give a yellow-orange solid assumed to be the bis trifluoroacetic acid salt, 30 mg, (4%); MS (ES +): m/z 535.1 (M+H).
Reaction SMILES: C(O)C.C([O-])(O)=O.[Na+].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.Cl.[CH3:20][O:21][C:22](=[O:27])[C@H:23]([CH2:25][SH:26])[NH2:24]>O>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]2[NH:24][C@H:23]([C:22]([O:21][CH3:20])=[O:27])[CH2:25][S:26]2)[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)[C@@H]1CSC(c2ccc(O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
In a co-solvent of ethanol (5 mL) and water (5 mL), a solution including NaHCO3 (486 mg, 5.79 mmol), 3,4-dihydroxybenzaldhehyde (3,4-dihydroxybenzaldehyde) (800 mg, 5.80 mmol), and L-cysteine methyl ester hydrochloride (1.0 g, 5.84 mmol) was stirred at room temperature for 5 hours. After ethanol was evaporated, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (4:1) to obtain a solid Compound 104 (1.23 g, 83%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:13]=[C:14]([C:18]2([CH:33]=O)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:18]2([CH:33]=[CH2:1])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=CC1(c2cccc(Br)c2)CCN(C(=O)OCc2ccccc2)C1
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1(c2cccc(Br)c2)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
KHMDS (0.5M in toluene, 6.536 mL, 3.268 mmol) was added to a suspension of Ph3PCH3Br (1.216 g, 3.404 mmol) in THF (15 mL) at rt. After 1 h, benzyl 3-(3-bromophenyl)-3-formylpyrrolidine-1-carboxylate was added at −20 and then the cold bath was removed. After 2 h, the reaction was quenched with MeOH (2 mL) and sat. aq. sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate and then dried (MgSO4), filtered and concentrated.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:31]([OH:32])=[C:30]([C:33]([NH:35][CH3:36])=[O:34])[CH:29]=[CH:28][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH2:25][CH2:26][CH3:27])=[C:14]([CH:22]=[CH:23][CH:24]=2)[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3][CH2:2]1.[CH3:37]OS(OC)(=O)=O.[OH-].[K+]>C1COCC1>[CH:1]1([CH2:4][C:5]2[C:31]([O:32][CH3:37])=[C:30]([C:33]([NH:35][CH3:36])=[O:34])[CH:29]=[CH:28][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH2:25][CH2:26][CH3:27])=[C:14]([CH:22]=[CH:23][CH:24]=2)[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3][CH2:2]1
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CC2CC2)cccc1OCC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CC2CC2)cccc1OCC(=O)OCC

Procedure:
The compound of Example 63 is methylated (Me2SO4, KOH, THF) under the conditions described in Example 45. Chromatographic purification of the crude product on silica gel (Ethyl acetate/hexane (3:7) as eluant) affords the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[C:17]1([NH2:24])[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>CO>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:23][C:20]1[CH:21]=[CH:22][C:17]([NH2:24])=[CH:18][CH:19]=1)(=[O:6])=[O:5]
Reactant: Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Solvent: CO
Product: Nc1ccc(Nc2ccc([N+](=O)[O-])cc2S(=O)(=O)CCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone are added at 65° C. under nitrogen to a solution of 118.8 g of 1,4-phenylenediamine in 500 ml of methanol in the course of 30 minutes. The reaction solution is stirred at this temperature for a further 4 hours and is then allowed to cool down to room temperature, and the reaction product is crystallized by addition of 1 l of ice-water. Filtering with suction and drying gives 168 g of 2-(4-aminophenylamino)-5-nitrophenyl hydroxyethyl sulfone having a melting point of 147°-149° C. and a purity of >99%, which corresponds to a yield of 99% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[C:21]([NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][OH:39])[CH:31]=3)[C:20]=2[CH3:41])=[O:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].O>N1C=CC=CC=1>[NH2:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[C:21]([NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][O:39][S:1]([CH3:4])(=[O:3])=[O:2])[CH:31]=3)[C:20]=2[CH3:41])=[O:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OCCO)c3)c3ccccn23)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OCCOS(C)(=O)=O)c3)c3ccccn23)ccc1N
Temperature: -20 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
59 μl (0.77 mmol) of mesyl chloride are added to the solution of 0.34 g (0.69 mmol) of methyl 2-amino-5-[(1-{[3-(2-hydroxyethoxy)benzoyl]amino}-2-methylindolizin-3-yl)carbonyl]benzoate in 9 ml of pyridine at −20° C. under nitrogen. The reaction mixture is stirred for 2 hours at −20° C. and is then run into 100 ml of water. The precipitate obtained is filtered, washed thoroughly with water and dried under vacuum, to give 268 mg (70%) of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][C:28]([O:30]C)=[O:29]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: COC(=O)CCc1ccccc1OCCCBr
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.4406 g, 10.5 mmol) in DMF (4 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of methyl 3-(2-(3-bromopropoxy)phenyl)propanoate (0.9035 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was diluted with water followed by extraction with dichloromethane. The aqueous layer was neutralized with dil. HCl to give white solid. Recrystallization from acetone afforded the desired diaminopyrimidine as white solid (0.6271 g, 58%, m.p. 155.5-157.5° C.). 1H NMR (400 MHz, DMSO-d6): 1.04 (3H, t, J=7.6 Hz), 2.19 (2H, m), 2.39 (2H, q, J=7.5 Hz), 2.46 (2H, t, J=7.5 Hz), 2.78 (2H, t, J=7.7 Hz), 3.83 (2H, t, J=6.1 Hz), 4.15 (2H, t, J=5.9 Hz), 6.29 (2H, bs), 6.85 (1H, t, J=7.4 Hz), 6.96 (2H, bs), 6.98 (1H, d, J=8.1 Hz), 7.14-7.19 (2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C=O)C>[Si:12]([O:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(=O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)CCO[Si](C)(C)C(C)(C)C
Yield: 94 %

Procedure:
4-Hydroxybutan-2-one (1.0 g, 11.35 mmol), imidazole (1.16 g, 17 mmol) in DMF (15 ml) was reacted with tert-butyldimethylsilyl chloride (1.7 g, 11.35 mmol) for three hours at room temperature. The reaction was partitioned with ether and water. The aqueous phase was extracted several times with ether. The combined organics were washed several times with water then dried over magnesium sulfate and concentrated in vacuo to give the title compound as a clear oil (2.16 g, 94%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([S:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCc3ccccc3)nc1-2
Yield: 21 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and benzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 21%.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH3:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O)=[O:6])[CH:2]=[CH2:3].[N:16]1(O)[C:20]2[CH:21]=CC=C[C:19]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)(C)C>ClCCl>[CH:20]([NH:16][C:13]([C@H:8]1[CH2:9][CH2:10][CH:11]([CH3:12])[N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:15])([CH3:21])[CH3:19]
Reactant: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)N
Product: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-(Allyloxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (0.92 g, 4.3 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.70 g, 5.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol), and isopropylamine (0.44 mL, 5.2 mmol) were dissolved in dichloromethane (2 mL) and stirred at ambient temperature for 16 h. The reaction was diluted with dichloromethane (100 mL), washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 255(M+H)+.