Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(COC([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]2)[CH2:25][CH2:24]1.[H][H]>CO.[Pd]>[CH:16]1[CH:15]=[CH:14][C:13]([C@@H:12]([NH2:11])[C:19]([OH:21])=[O:20])=[CH:18][CH:17]=1.[CH3:22][N:23]1[CH2:24][CH2:25][CH:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:28]1
Reactant: [H][H]
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: CN1CCC(C2CCN(C(N)=O)CC2)CC1
Solvent: CO
Product: N[C@@H](C(=O)O)c1ccccc1

Procedure:
A vigorously stirred solution of CBz-D-phenylglycine-4-(1-methylpiperidin-4-yl)piperidinamide (1.1 g, 2.45 mmol) in methanol (120 ml), containing Palladium on carbon (200 mg ) was treated with hydrogen gas (balloon) at atmospheric pressure overnight. The reaction mixture was filtered through celite and concentrated to yield the title compound as a colourless oil (585 mg, 76%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH:21]=[CH2:22])=[CH:15][CH:16]=2)[C:11]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH3:22])=[CH:15][CH:16]=2)[C:11]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Solvent: O
Solvent: CC#N
Product: CCc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2-yl)acetic acid (93) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.59 (s, 1H), 7.53 (m, 2H), 7.29 (m, 2H), 7.04 (s, 1H), 5.07 (s, 1H), 2.60 (m, 5H), 1.15 (t, J=7 Hz, 3H), 0.94 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.81.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:26])[O:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:27]([N:26]=[C:16]([N:7]1[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[O:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)NCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)NCCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 2-ethoxycarbonylamino-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and benzoyl chloride, there is obtained 2-ethoxycarbonylamino-ethyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 457 (6), 341 (18), 194 (100), 116 (75), 105 (75);
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[C:14](Cl)(Cl)=[O:15]>O1CCOCC1>[Cl:1][C:2]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][CH:6]=[C:5]([Cl:13])[C:3]=1[N:4]=[C:14]=[O:15]
Reactant: Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=C=Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-trifluoromethyl-aniline (138 mg, 0.60 mmol) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture is stirred for 2 h at 100° C., cooled to rt and concentrated in vacuo, yielding 2,6-dichloro-3-trifluoromethyl-phenylisocyanate.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[C:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24](=O)/[CH:25]=[CH:26]/N(C)C)[CH:21]=[CH:20][C:19]=1[O:31][CH3:32])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(O)(=O)C>[C:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][C:3]3[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=3[N:1]=2)[CH:21]=[CH:20][C:19]=1[O:31][CH3:32])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(=O)/C=C/N(C)C)cc1COC(=O)C(C)(C)C
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2ccc3c(=O)[nH]c(=O)[nH]c3n2)cc1COC(=O)C(C)(C)C
Temperature: 99 °C
Reaction time: 0.83 h
Yield: 91.7 %

Procedure:
6-Aminouracil (2.50 g, 19.1 mmol) was added to glacial acetic acid (24.6 mL) and water (6.1 mL) and the mixture heated to 99° C. A solution of 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzyl pivalate (3.1 g, 9.5 mmol) in DMSO (9.2 mL) was then added over 280 minutes. The reaction was stirred at 99° C. for a further 50 minutes and cooled to 0° C. A solution of potassium hydroxide (24 g, 363.6 mmol) in water (48 mL) was then added to achieve a pH of around 7.0. Aqueous potassium carbonate was then added to afford a pH of around 10. After an hour at RT, a beige solid was filtered off, washed three times with aqueous potassium carbonate and pulled visibly dry on the filter. The beige solid was then added to a solution of citric acid (7.1 g) in water (44 ml) and the mixture maintained at 20° C. for 60 minutes. The resulting creamy white solid was isolated by filtration and washed with water until neutral pH of the wash liquors was obtained. The solid was dried to constant weight in vacuo thus affording 3.34 g of desired product (3).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=[O:16])=[O:15])[CH3:3].CC(C)([O-])C.[K+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(#N)C>[Cl:23][CH2:24][C:25]([N:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9](=[O:10])[N:4]([CH:2]([CH3:1])[CH3:3])[S:5]1(=[O:16])=[O:15])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(=O)c2ccccc2N(C(=O)CCl)S1(=O)=O

Procedure:
To 100 ml of acetonitrile was added 10.0 g of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one- -2,2-dioxide and 4.9 g of potassium t-butoxide. The mixture was stirred vigorously and 3.3 ml of chloroacetyl chloride in 50 ml acetanitrile was added dropwise over a 0.5 hour period. The resultant mixture as stirred overnight, filtered and the solvent removed from the filtrate in vacuo. The residue was washed with carbon tetrachloride and filtered. The tan granular precipitate was dissolved in 50 ml of methylene chloride and 50 ml of carbon tetrachloride was added. The methylene chloride was removed under a nitrogen atmosphere and the resultant mixture was filtered. The precipitate was washed 5% aqueous potassium carbonate, filtered and the white flocculent precipitate air dried to afford 2.23 g of 1-(2-chloroacetyl)-3-(1-methylethyl)- -1H-2,1,3-benzothiadiazin-4 (3H)-one-2,2-dioxide, m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][CH2:9]Cl)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[N:15]1([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][CH2:9][N:18]2[CH2:19][CH2:20][N:15]([C:21]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]4)=[O:22])[CH2:16][CH2:17]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)N3CCN(CCC(=O)c4ccc(Cl)cc4)CC3)ccc2N1
Temperature: 50 °C

Procedure:
4.12 Grams of 2-(4-chlorobenzoyl)ethyl chloride and 6.08 g of sodium iodide were dispersed in 50 ml of dimethylformamide, and heated at 50° C. for 1.5 hours. Then, to this dispersion was added 50 ml of dimethylformamide solution containing 3 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, and further 9.8 g of potassium carbonate was added thereto and reacted by heating at 70° C. for 3 to 4 hours. After the reaction was completed, the insoluble matters were removed by filtration, and the solvent in the filtrate was removed by evaporation under reduced pressure. The residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous calcium sulfate, then concentrated. The thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =50:1), then recrystallized from ethanol-diethyl ether to yield 2.29 g of 6-{4-[2-(4-chlorobenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril. White powdery substance. Melting point: 198° C.-200° C. (decomp.)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+].Cl>C(O)C.O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OCCC[Si](C)(C)C)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCCOc1ccc(O)c(C(=O)O)c1
Yield: 62.1 %

Procedure:
The product of Example 3 (3.3 g, 0.012 mol) in a 50/50 ethanol/water mixture (15 ml) was maintained at reflux for 3 hours in the presence of potassium hydroxide (2 g). The mixture was cooled and acidified to pH 1 with 10% hydrochloric acid. The precipitate formed was washed with water and dried under vacuum. It was recrystallized from a 50/50 methanol/water mixture (30 ml). 2 g (yield: 64%) of 2-hydroxy-5-(3-trimethylsilanylpro-pyloxy)benzoic acid were obtained in the form of a white powder.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:22])[C:10]([C:13]#[C:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:11][CH:12]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.CCOC(C)=O>C(OCC)C>[Si:15]([C:14]#[C:13][C:10]1[N:11]=[CH:12][C:7]([C:27]2([OH:30])[CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:8][C:9]=1[F:22])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Reactant: CC1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1CCC(O)(c2cnc(C#C[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Under an argon atmosphere 9.38 mL (15.0 mmol, 1.6 M) of n-butyllithium was slowly added to a solution of 4.71 g (15.0 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]-3-fluoropyridine in 100 mL of diethyl ether at −70° C., so that the internal temperature did not rise above −65° C. After 2 minutes, 1.84 mL (15.0 mmol) of 4-methylcyclohexanone was added and then the cooling bath was removed. The reaction solution was heated to RT and then combined with 50 mL of aqueous saturated ammonium chloride solution. The organic phase was separated off, the aqueous phase was extracted twice with MTBE, and the combined organic phases were dried over magnesium sulfate, filtered through activated charcoal, and the solvent was removed in vacuo. The residue was taken up in DIPE, cooled in the cooling bath, and the precipitate formed (1.4 g) was suction filtered. The mother liquor was concentrated in vacuo and the residue was purified by column chromatography (silica gel, PE/EtOAc 8:2). A further 2.1 g were obtained, which were combined with the above precipitate. The product was obtained as a cis/trans mixture. Yield: 3.50 g (67% of theoretical); C20H30FNOSi (M=347.542); calc.: molpeak (M+H)+:348; found: molpeak (M+H)+:348; Rf value: 0.5 (silica gel, PE/EtOAc 8:2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:13][CH2:12][C:11](=O)[NH:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.B.B.O1CCCC1>O1CCCC1.CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COC(c2cccc(Cl)n2)CN1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Clc1cccc(C2CNCCO2)n1
Reaction time: 1 h

Procedure:
1 g (0.0047 mol) of 2-(6-chloro-pyridin-2-yl)-morpholin-5-one are dissolved in 20 ml of absolute tetrahydrofuran, added with stirring at ambient temperature to 5 ml of a 1 molar solution of borane in tetrahydrofuran and the reaction solution is stirred for 60 minutes. Then sufficient borane/tetrahydrofuran solution is added in batches until all the starting material has reacted, according to thin layer chromatography. The solvent is then drawn off, the residue is stirred in 20 ml of methanol for 18 hours and then evaporated down. This residue is taken up in 20 ml of 2N hydrochloric acid and stirred at 50° C. for 2 hours. The acid solution is cooled in an ice bath, made alkaline with ammonia solution and extracted with methylene chloride. The organic phase is dried over sodium sulphate, concentrated by evaporation and the residue is purified over a silica gel column with methanol as eluant.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@@:13]([OH:24])([CH3:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C.[I-].[Na+]>C(#N)C.CN(C=O)C>[OH:24][C@:13]1([CH3:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][O:35][C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)[CH2:12]1
Reactant: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc4ccc([N+](=O)[O-])cc4)CC[C@@H]32)C1
Yield: 51.3 %

Procedure:
A solution of 21-bromo-3α-hydroxy-3β-methyl-5α-pregnan-20-one (250 mg, 0.61 mmol), 4-nitrophenol (127 mg, 0.912 mmol), triethylamine (127 μL,0.912 mmol), and a small amount of sodium iodide in 2:1 acetonitrile DMF was stirred with heating to ~60° C. for 6 hours. The mixture was partitioned between EtOAc and 1:1 water:sat. aq. sodium bicarbonate. The organic layer was washed with 2N HCl, water and sat. aq. NaCl, dried with Na2SO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 20% acetone in hexane yielded 3α-hydroxy-3β-methyl-21-(4'-nitrophenoxy)-5α-pregnan-20-one (147 mg) as a solid; mp 169-172° C.; TLC Rf (hexane:acetone 4:1)=0.35.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]C)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCC=CCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (g, mmol) was reacted with N-(2-azidoethyl)octadec-9-enamide (g, mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-heptadec-8-enamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), δ 6.81 (s, 1H), δ 6.42 (s, 2H), δ 5.88 (s, 1H), δ 5.27 (s, 2H), δ 4.38 (s, 2H), δ 3.65 (s, 2H), δ 2.60 (s, 2H), δ 2.09 (s, 2H), δ 1.53-1.01 (m, 35H), 0.79 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.2, 173.8, 148.3, 130.3, 130.1, 129.9, 129.8, 121.9, 85.1, 67.1, 49.5, 39.5, 39.1, 38.0, 37.7, 36.7, 36.6, 32.8, 32.3, 32.1, 31.7, 29.9, 29.8, 29.7, 29.5, 29.3, 29.2, 28.9, 28.7, 28.1, 28.0, 27.9, 27.4, 27.3, 27.3, 26.9, 25.9, 25.6, 25.3, 22.9, 22.8, 22.6, 14.3, 14.2 ppm; HRMS (ESI) calcd for C35H61N7O3 (M+) 627.4836, found 627.4823, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)heptadec-8-enamide hydrochloride (0.128 g, 66% yield). 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), δ 6.96 (s, 1H), δ 6.45 (s, 1H), δ 6.09 (s, 1H), δ 4.58 (s, 2H), δ 3.58 (s, 2H), δ 2.75 (s, 2H), δ 2.10 (s, 2H), δ 1.96 (s, 4H), δ 1.69 (s, 2H), δ 1.41 (m, 4H), 1.23 (s, 24H), δ 0.84 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.5, 158.8, 155.7, 147.3, 129.7, 129.6, 127.6, 108.5, 94.6, 76.7, 51.3, 50.4, 48.6, 48.4, 48.2, 47.9, 47.8, 47.5, 47.3, 38.9, 37.5, 36.6, 45.9, 45.8, 33.9, 32.6, 31.9, 31.5, 29.8, 29.5, 29.4, 29.3, 29.2, 29.1, 28.2, 27.8, 27.0, 25.8, 24.9, 24.2, 23.8, 22.5, 13.5, 13.3 ppm; HRMS (ESI) calcd for C30H53N7O (M+) 527.4312, found 527.4298.
Reaction SMILES: C(O)(=O)C.C(OC([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:22][N:23]3[CH2:27][CH2:26][N:25]=[CH:24]3)[C:19]=2[CH3:21])[CH2:14][CH2:13]1)=O)(C)(C)C.Br.C(O)(=O)C.CO>C(Cl)Cl>[N:23]1([NH:22][C:18]2[C:19]([CH3:21])=[C:20]3[C:15]([CH2:14][CH2:13][NH:12]3)=[CH:16][CH:17]=2)[CH2:27][CH2:26][N:25]=[CH:24]1
Reactant: Cc1c(NN2C=NCC2)ccc2c1N(C(=O)OC(C)(C)C)CC2
Agent: Br
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(NN2C=NCC2)ccc2c1NCC2
Reaction time: 2.5 h

Procedure:
A solution of 1-t-butoxycarbonyl-2,3-dihydro-6-(2-imidazolinylamino)-7-methylindole acetic acid salt (0.69 g, 1.85 mmol) in methylene chloride (7 mL) is treated dropwise with a 30% solution of hydrogen bromide in acetic acid (1.0 g, 3.7 mmol). A precipitate forms which dissolves upon addition of 2 mL of methanol. The reaction is stirred for 2.5 hours then concentrated under a stream of nitrogen. The material is diluted with water, and chloroform and brought to pH=14 with 1 M aqueous sodium hydroxide solution. The chloroform layer is collected and the aqueous solution extracted two additional times with chloroform. The combined organic extracts are dried over potassium carbonate, filtered and the filtrate evaporated on a rotary evaporator to afford 2,3-dihydro-6-(2-imidazolinylamino)-7-methylindole.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[N:42]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4[CH2:21][C:20](=[O:22])[NH:19][C:18]5[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=5[N:16]=4)[CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:5][N:4]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(CN4CCCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with pyrrolidine in DMF according to the general procedure of example 288. Obtained as a light brown solid (225 mg, 80%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.N1C=CC=CC=1.CN(C)[CH:18]=[O:19].C(OC(=O)C)=O>O>[CH:18]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)=[O:19]
Reactant: Nc1nc(CCl)cs1
Reactant: CN(C)C=O
Agent: CC(=O)OC=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=CNc1nc(CCl)cs1

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (2 g), anhydrous pyridine (3.2 g) and anhydrous N,N-dimethylformamide (10 ml) was slowly added acetic formic anhydride (1.7 g) with stirring at 0° to 5° C. After one hour of stirring, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and aqueous sodium chloride solution successively and dried over magnesium sulfate. The solvent was then distilled off and the residue was collected and dried to give 2-formylamino-4-chloromethylthiazole (0.94 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[C:3]([O:11][CH2:21][O:22][CH3:23])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: COCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCOc1c(Cl)cc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
3,5-Dichloro-2-hydroxy-benzaldehyde (200 mg, 1.57 mmol) was placed in a 20 mL reaction vessel, and dissolved in 4.7 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol), and chloromethyl methyl ether (149 μL, 1.96 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 100 mL of ethyl acetate and 20 mL of 1N HCl, and extracted. The organic layer was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a white solid (314.4 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=2)[N:19]=[CH:18][N:17]=1>O1CCCC1.C(Cl)(Cl)Cl.O.[Cl-].[Na+].O>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:31][CH2:32][CH2:33][O:34][CH3:35])[N:19]=[CH:18][N:17]=[C:16]2[S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: Nc1cccc(S)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
3-Aminothiophenol (56 mg, 0.45 mmol) was treated with cesium carbonate (193 g, 0.59 mmol) in anhydrous tetrahydrofuran (22 mL) and the mixture stirred at room temperature for 30 minutes. 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (142 mg, 0.45 mmol) from Example 12A was added and the mixture stirred at 60° C. overnight. After cooling to room temperature the mixture was diluted with chloroform, water and brine were added and the organic phase separated. The water phase was extracted three times with chloroform, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol 9:1) to afford 3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)aniline (140 mg, 77%) as a solid. 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 7.41 (s, 1H), 7.26 (t, 2H), 6.99-6.94 (m, 2H), 6.74 (d, 1H), 4.30 (s, 4H), 3.99 (bs, 6H), 3.87 (s, 6H); LC-MS (ESI) m/z 402 (M+H)+.