Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:35]([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH3:36]>CN(C=O)C>[CH:38]1([N:37]([CH2:35][CH3:36])[C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)=[O:3])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCNC1CCCCC1
Reactant: CC(COc1cccc2c1CCC(=O)N2)CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(C(=O)CC(C)COc1cccc2c1CCC(=O)N2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.3 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 0.8 ml of triethylamine are added to 50 ml of DMF, and the mixture is added dropwise with 0.65 ml of isobutyl chloroformate under external ice cooling and agitation at internal temperature of 0° to 10° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added dropwise with 0.7 g of N-ethylcyclohexylamine and further agitated at room temperature for 2 hours. The solvent is distilled off and the residue is dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid, aqueous K2CO3 solution and water in that order and then dried with anhydrous Na2SO4. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene to obtain 0.8 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 114°-115.5° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][S:24][C:25]1[N:30]=[C:29]([NH:31][S:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:28]=[C:27]([O:41][CH3:42])[N:26]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:38]1[CH2:37][CH2:36][N:35]([S:32]([NH:31][C:29]2[CH:28]=[C:27]([O:41][CH3:42])[N:26]=[C:25]([S:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=3[F:15])[N:30]=2)(=[O:34])=[O:33])[CH2:40][CH2:39]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NS(=O)(=O)N2CCN(C(C)=O)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.78 mL) was added to a mixture of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the title product of Example 36, 0.84 g) and N,N-diisopropylethylamine (1 mL) in DCM (5 mL). The reaction mixture was stirred at room temperature for 30 min and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc which was washed with aqueous citric acid, H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with EtOAc to give the title compound as a white solid. Yield: 78 mg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]([C:20]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([NH:6][CH:7]([C:20]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:4])=[O:3]
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(NS(C)(=O)=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methanesulfonyl chloride (37 μl, 0.48 mmol) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (134.6 mg, 0.4 mmol) and triethylamine (67 μl, 0.48 mmol) in dichloromethane (2 ml) at 0°. Stirring continued overnight (14 hours) while the cooling both attained room temperature. The reaction mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 10% ethyl ether/hexane. Fractions with Rf of about 0.07 on evaporation gave the title sulfonamide as a pale yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([OH:13])(=[O:12])[CH2:10][CH3:11].C([O-])(=O)CC.[K+]>>[CH3:11][CH:10]1[CH2:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:13][C:9]1=[O:12]
Reactant: CCC(=O)O
Reactant: C=CCCCCCC
Agent: CCC(=O)[O-]
Agent: [K+]
Product: CCCCCCC1CC(C)C(=O)O1

Procedure:
Octene-1 in an amount of 2.24 g. and 11.65 g. of manganic acetate, Mn(C2H3O2)3.2H2O, (comprising two equivalents of Mn+3 based on titration value), were refluxed under nitrogen in 200 ml. propionic acid containing 20 g. potassium propionate. In less than an hour a good yield of alphamethyl-gamma-n-hexyl-butyrolactone was obtained.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]3=[O:36])=[CH:22][C:21]=2[F:37])([OH:17])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[F:37][C:21]1[CH:22]=[C:23]([N:26]2[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]2=[O:36])[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:14]1([OH:17])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNCC3)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A suspension of 31 g of 4-{4-[(5S)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluorophenoxymethyl}-4-hydroxypiperidin-1-carboxylic acid benzyl ester (MW: 515.54, 60.13 mmol) and 2.5 g of palladium (10% on activated carbon) in 310 ml of methanol and 150 ml of ethyl acetate was stirred for 4 h under a hydrogen atmosphere. The course of the reaction was monitored by TLC (ethyl acetate). The suspension was diluted with 300 ml of methanol, heated to 40° C., and the catalyst was filtered off through a fibreglass filter paper. The filtrate was concentrated to 150 ml, diluted with 300 ml of ethyl acetate and concentrated again to 200 ml. 200 ml of diethyl ether were added and the suspension was cooled, with stirring, to 0° C. The solid material was collected and dried. Yield: 21.6 g, 94.3%. MS: 382.6 (M+H)+, Method: ESI+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:12].N([O-])=O.[Na+].[S:17](=[O:19])=[O:18]>C(O)(=O)C.O>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([S:17]([Cl:12])(=[O:19])=[O:18])=[CH:3][CH:4]=1)(=[O:10])(=[O:9])[NH2:11]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 0.17 h

Procedure:
6.4 g (37.2 mmol) of 4-aminobenzenesulfonamide was added to a mixed solution of 12.5 ml of water and 6.3 ml of concentrated hydrochloric acid, followed by stirring. An aqueous saturated solution containing 2.56 g (37.1 mmol) of sodium nitrite was added drop wise there into at 0° C. or less. The reaction solution was added to an acetic acid solution saturated with sulfur dioxide (solution obtained by saturating 35 ml of acetic acid with sulfur dioxide and then adding 1.5 g of cupric chloride dihydrate thereto) under ice-cooling with stirring. After 10 minutes, the reaction solution was poured into ice-water, and the precipitates were collected by filtration and washed with water. The precipitates were dissolved in tetrahydrofuran, dried over magnesium sulfate and then concentrated to dryness, to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14]CC[Si](C)(C)C)[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26]([OH:28])[OH:27].CCN(C(C)C)C(C)C.C/C(/[O:46][Si](C)(C)C)=N\[Si](C)(C)C.C1C=C(SSC2N=CC=CC=2)N=CC=1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26](=[O:46])([OH:28])[OH:27]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(O)O)C(=O)OC2
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(O)c1CC=C(C)COP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phosphorous acid mono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl} ester (27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12 mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at room temperature for 3 hours. To the reaction solution was added 2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowed to stir for an additional 2 hours at room temperature. The reaction mixture was diluted by addition of H2O and the solution was stirred for 2 more hours when it was concentrated. The residue was dissolved in a solution of 10% TFA/CH2Cl2 and stirred at room temperature for 9 hours. The reaction mixture was dried under reduced pressure and the product was purified by reverse-phase HPLC to provide the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H), 5.50-5.61 (m, 1H); 31P (121.4 MHz, CD3OD) δ 0.50; MS (m/z) 357 [M−H]−.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C@@H:15]([CH3:23])[C@H:16]([OH:22])[C:17](OCC)=[O:18])=[CH:9][NH:10]2.Br.[CH3:25][NH:26][C:27](NC)=[NH:28]>O>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH:15]([CH:16]1[O:22][C:27]([NH:26][CH3:25])=[N:28][C:17]1=[O:18])[CH3:23])=[CH:9][NH:10]2
Reactant: CNC(=N)NC
Reactant: CCOC(=O)[C@@H](O)[C@H](C)c1c[nH]c2cccc(Cl)c12
Agent: Br
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(Cl)c23)O1
Yield: 12.1 %

Procedure:
Sodium (100 mg) was dissolved into ethanol (5 ml). Ethyl (2S*,3R*)-3-(4-chloroindol-3-yl)-2-hydroxybutyrate (200 mg) and N,N′-dimethyl guanidine hydrogen bromide (143 mg) were added. The whole was refluxed for 16 hours. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided the titled compound (25 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43](I)[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][N:37]=[C:36]2[NH:35][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:20]([Cl:19])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester is prepared by adding prop-2-ynyl-carbamic acid tert-butyl ester (0.978 g, 6.31 mmol), diisopropylamine (1.77 ml, 12.63 mmol), Pd(PPh3)2Cl2 (210 mg, 0.30 mmol) and CuI (57 mg, 0.30 mmol) to a stirred solution of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine (3.11 g, 5.74 mmol) in THF (40 ml). After stirring the reaction mixture at rt under N2 for 3 h, the THF is removed under reduced pressured and methylene chloride is added. The organic layer is washed with NH4Cl (salt) and brine, and dried (Na2SO4). The solvent is evaporated and the residual solid is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH:51]2[CH2:53][CH2:52]2)[C:34]([NH:40][C@H:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][C@@H:42]2[OH:50])=[N:35][C:36]=1[CH:37]1[CH2:39][CH2:38]1>>[CH:51]1([C:33]2[C:34]([NH:40][C@@H:41]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:43][C@@H:42]3[OH:50])=[N:35][C:36]([CH:37]3[CH2:39][CH2:38]3)=[C:31]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[Cl:8])[N:32]=2)[CH2:53][CH2:52]1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O[C@H]1Cc2ccccc2[C@@H]1Nc1nc(C2CC2)c(Br)nc1C1CC1
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (1S,2S)-1-[(5-bromo-3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.85-0.99, 1.67, 1.82, 2.48, 3.10-3.13, 3.27-3.28, 4.79, 5.40, 5.42, 7.30-7.51; MS (ESI+) for C25H23Cl2N3O m/z 452 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH2:13]([O:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:37][C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])[CH3:14]>O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH2:13]([O:15][C@@H:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:37][C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][CH:26]=1)[C:17]([O-:19])=[O:18])[CH3:14]
Reactant: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)[O-]

Procedure:
(L)-Arginine (124.6 mg, 0.72 mmol) was dissolved in water (½ ml) at 50-60° C. and added to the solution of (2S)-2-Ethoxy-3-{4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl}propanoic acid, heated to reflux.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]#[N:8].[C:9]1([CH3:20])[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(#N)C>[C:9]1([CH3:20])[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][N+:2]1([CH3:9])[CH3:1])#[N:8]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CCCC1C#N
Solvent: CC#N
Product: C[N+]1(C)CCCC1C#N
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
In a 250 mL round bottomed flask equipped with a magnetic stir bar, reflux condenser, and pressure-equalizing addition funnel, 10 mmol of 1-methyl-2-pyrrolidinecarbonitrile (16, prepared according to Chiba, et. al., J. Org. Chem. 1977, Vol. 42, No. 18, pp. 2973–7) is dissolved in 50 mL acetonitrile. The mixture is cooled with an ice bath and 10 mmol methyl p-toluenesulfonate (15, available from Aldrich Chemical Company, Inc., Milwaukee, Wis., 53233) is added slowly with stirring under an argon atmosphere. Once the addition is complete, the ice bath is removed and the reaction is warmed to reflux, stirred 16 h, then cooled to room temperature. The solvent is then removed under reduced pressure to obtain 17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][NH2:43])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:43][CH2:42][CH2:41][CH2:40][C:37]3[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][CH:38]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18]Br)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:20])[CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: N#Cc1ccc2[nH]cc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(C#N)ccc21
Temperature: 80 °C
Yield: 90.3 %

Procedure:
A mixture of 3-chloro-1H-indole-5-carbonitrile (D94) (1.8 g, 10 mmol), ethyl-3-bromopropionate (1.92 ml, 15 mmol), cesium carbonate (6.5 g, 20 mmol) and DMF (50 ml) was heated at 80° C. for 4 hours to give complete reaction. After allowing mixture to cool to room temperature diethyl ether (300 ml) was added and the solution washed with water (3×300 ml). Dried over MgSO4 and evaporated off the solvent to give a brown solid. The solid was triturated with a mixture of diethyl ether and hexane to obtain 2.5 g of the title compound as a tan solid. Crude product used in the next stage (synthesis of D96).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:26]1[O:28][CH2:27]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:26]([OH:28])[CH2:27][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
2.576 g of N-tert.butyl-2(S)-piperidinecarboxamide and 4.158 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 70 ml of ethanol was heated at reflux for 16 hours. The solvent was removed by evaporation and the residue was dissolved in 100 ml of diethyl ether and treated with 10 g of activated magnesium silicate. The solvent was then removed by evaporation and there were obtained 6.16 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide as a colourless glass; MS: m/e 482 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](I)[CH3:10].C(=O)([O-])[O-].[K+].[K+].C([Li])CCC.CON(C)[C:26]([C:28]1[C:29]([NH2:37])=[N:30][C:31]([S:34][CH2:35][CH3:36])=[N:32][CH:33]=1)=[O:27]>CC(C)=O>[NH2:37][C:29]1[C:28]([C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH2:9][CH3:10])=[O:27])=[CH:33][N:32]=[C:31]([S:34][CH2:35][CH3:36])[N:30]=1
Reactant: Oc1ccccc1I
Reactant: CCI
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: CCOc1ccccc1C(=O)c1cnc(SCC)nc1N

Procedure:
The product of the reaction of 2-iodophenol (Aldrich) and ethyl iodide in hot acetone containing potassium carbonate was treated with n-butyl lithium as described in Example 2A and subsequently reacted with 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, using the procedure of Example 47 to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-ethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 304
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=[O:9])[S:4][N:3]=1.[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>O1CCCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([O-:10])=[O:9])[S:4][N:3]=1.[CH2:11]([NH+:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[NH+](CC)CC
Product: O=C([O-])c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of dry tetrahydrofuran, 1.0 g of the 3,4-dichloro-5-isothiazolecarboxylic acid obtained in Example 2 was dissolved, followed by the dropwise addition of a solution of 0.52 g of triethylamine in 5 ml of dry tetrahydrofuran. After the resulting mixture was stirred further at room temperature for 30 minutes, the solvent was distilled off under reduced pressure so that 1.51 g (stoichiometric amount) of the title compound were obtained.
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[NH:3][CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[O:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[O:17][CH2:18][CH2:19][CH2:20][NH:21][C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:9]1)=[O:12]
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Reactant: NCCCOc1cccc(Cl)c1
Product: Cl
Product: O=C(NCCCOc1cccc(Cl)c1)C1CCc2[nH]cnc2C1

Procedure:
By a similar procedure as described in Example 65, the title compound was prepared from 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid and 3-(3-chlorophenoxy)propylamine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH2:23][C:22]1=[O:31].CO>C(#N)C>[CH2:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH2:23][C:22]2=[O:31])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C1CSc2ccccc2N1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CCCCC1CCN(CCCN2C(=O)CSc3ccccc32)CC1
Reaction time: 13 h

Procedure:
NAI (1.24 g, 8.27 mmol), K2CO3 (1.14 g, 8.27 mmol), and 4-butylpiperidine (0.62 g, 4.34 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]thiazin-3-one (1.0 g, 4.14 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60 C. for 13 hours and then 80 C. for another 25 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.63 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield 1.06 g 74.2% HPLC-MS [M+H]+347 (UV/MS(%)=100/99. 1H NMR (CDCl3): δ 0.88 (t, 3H), 1.23 (m, 9H), 1.64 (d, 2H), 1.85 (m, 4H), 2.34 (t, 2H), 2.83 (d, 2H), 3.36 (s, 1H), 4.03 (t, 2H), 6.99 (m, 1H), 7.22 (d, 2H), 7.34 (d, 1H), 13C NMR (CDCl3): δ 14.21, 23.03, 25.23, 29.15, 31.80, 32.63, 35.90, 36.44, 43.28, 54.26, 55.91, 118.18, 123.45, 124.17, 127.27, 128.56, 139.63, 165.19.