Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1>C1COCC1>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cccc(Cl)c2Cl)CC1
Agent: Cl
Solvent: C1CCOC1
Product: Clc1cccc(C2CCNCC2)c1Cl
Yield: 108.6 %

Procedure:
To 6 N HCl (30 mL) was added a solution of intermediate 46 (5.2 g, 14 mmol) in THF (10 mL). The mixture was heated to reflux for 3 h and then concentrated in vacuo. The residue was washed with Et2O to give 4-(2,3-dichlorophenyl)piperidine (intermediate 47) (3.5 g, 92%) as a white solid. HPLC: 99%, RT 2.149 min. MS (ESI) m/z 230.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:24][C:25]1[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([NH:24][C:25]2[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=2)[C:30]([O:32][CH3:33])=[O:31])=[O:13])[CH:7]=1
Reactant: O=C(O)c1cnn2cc(Br)ccc12
Reactant: COC(=O)c1cnc(C)c(N)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cnc(C)c(NC(=O)c2cnn3cc(Br)ccc23)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
6-Bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (7.71 g, 32.0 mmol) in toluene (80 ml) was treated with thionyl chloride (18.67 ml, 256 mmol) and was heated to 110° C. for 6 hr. The solvent was removed in vacuo and the residue was treated with pyridine (80 ml), methyl 5-amino-6-methylnicotinate (4.25 g, 25.6 mmol) and oven dried molecular sieves. The reaction mixture was stirred at RT overnight and then treated with MeOH (250 ml). The resulting suspension was removed by filtration. The filtrate was triturated with methanol and the solid produced was isolated to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]O)=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].O1CCCC1.CS(Cl)(=O)=O.O.[NH3:42]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][NH2:42])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: N
Reactant: OCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(tri-fluoromethyl)pyrimidin-5-yl}methanol (1.0 g) was added to tetrahydrofuran (30 mL), and then, under ice cooling, tetrahydrofuran solution (10 mL) comprising methanesulfonyl chloride (0.3 g) was added dropwise thereto. After the dropwise addition was completed, the solution was stirred at room temperature for one hour. The resulting solution was added dropwise to a mixture solution, which was separately prepared to comprise 28% ammonia water (50 mL), tetrahydrofuran (100 mL), and methanol (100 mL), under ice cooling. After the stirring for 12 hours at room temperature, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.4 g, 45%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl>[Cl:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 0 °C

Procedure:
Dissolve 5-chloro-pyrazine-2-carboxylic acid methyl ester (10.0 g, 57.9 mmol) in THF (65 mL) and MeOH (65 mL). Cool the solution to 0° C. before adding 1N NaOH (63.7 mL) with stirring. Warm the mixture to room temperature and stir for 5 h. Concentrate the mixture in vacuo to 1/3 volume. Quench with 1N HCl (75 mL) to form a white precipitate. Dilute with CH2Cl2 (200 mL) and filter. Wash the filter cake with water and CH2Cl2. Separate the phases, dry the organic phase over MgSO4, filter, and concentrate. Add the aqueous layer to the concentrated organic residue and concentrate. Purify by silica gel flash column chromatography, eluting with 40% ethyl acetate/n-hexane, followed by 10% MeOH, 3% acetic acid and 87%
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([N:8]1[CH2:11][C@H:10]([NH:12]C(OCC2C=CC=CC=2)=O)[C:9]1=[O:23])=[O:7])(=[O:4])=[O:3].CO.Cl>[Pd].O>[NH2:12][C@H:10]1[CH2:11][N:8]([C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[O:7])[C:9]1=[O:23]
Reactant: CS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)NC(=O)N1C[C@H](N)C1=O
Yield: 45.8 %

Procedure:
(S)-N-(Methylsulfonyl)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinecarboxamide (2.20 g; see example 5) was stirred with 90 ml of methanol under nitrogen at 40° to 45° C. until solution occurs. The solutions was quickly cooled to room temperature and hydrogenated at one atmosphere in the presence of 1.1 g of 10% palladium on charcoal for twenty minutes. Water (20 ml) was added, and the pH was adjusted to 2.0 (1N hydrochloric acid). The product, which was absorbed on the catalyst, was collected by filtration, using Whatman #50 paper, and suspended in 25 ml of water. The pH was adjusted to 2.0 (1N hydrochloric acid), and the mixture was stirred for twenty-five minutes and filtered through Whatman #50 paper. Evaporation of the filtrate provided 611 mg of crystalline product, melting point 180° C., dec.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[CH:10]=[CH:11]OCC>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:15])[CH:10]=[CH:11]2
Reactant: CCOC=CC(=O)Nc1ccccc1Br
Agent: O=S(=O)(O)O
Product: O=c1ccc2cccc(Br)c2[nH]1
Reaction time: 1 h

Procedure:
6 g (22.21 mmol) of N-(2-bromo-phenyl)-3-ethoxy-acrylamide are added batchwise to 30 ml of concentrated sulphuric acid (exothermic) and stirred for one hour. The reaction mixture is poured onto ice water and the precipitate formed is filtered off. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethyl acetate=3:1).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=2)=[CH:4][N:3]=1)=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=3.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>>[CH2:25]([S:22]([C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:14]4[CH:13]=[C:12]([CH3:15])[CH:11]=[N:10][C:9]=4[NH:8][C:7]=3[C:2]([NH:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[N:3][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CN(C)CCCN
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cnc(NCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
Compound 32 (16 mg, 0.041 mmol) was heated with 3-dimethylamino-1-propylamine (1 mL) at 206° C. in the microwave for 30 min. Purification by prep-HPLC gave 10.2 (55%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD-d4): δ 8.65 (br s, 1H), 8.17 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 7.98 (d, 1H, J=7.6 Hz), 7.91 (t, 1H, J=7.6 Hz), 7.67 (s, 1H), 7.66 (s, 1H), 3.80 (t, 2H, J=6.8 Hz), 3.28-3.43 (m, 4H), 2.96 (s, 6H), 2.29-2.38 (m, 5H), 1.28 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C24H29N5O2S, 452; found 452.
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:24])[S:7][C@@H:6]2[C@H:8]([NH:11][C:12]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])[C:9](=[O:10])[N:5]2[C@H:4]1[C:21]([OH:23])=[O:22].Br[CH:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=2)[C:28](=[O:29])[O:27]1>O>[CH3:37][O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH3:39])[C:28](=[O:29])[O:27][CH2:26]2.[CH3:2][C:3]1([CH3:24])[S:7][C@@H:6]2[C@H:8]([NH:11][C:12]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])[C:9](=[O:10])[N:5]2[C@H:4]1[C:21]([OH:23])=[O:22]
Reactant: COc1cc2c(cc1OC)C(Br)OC2=O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [K]
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)OC2

Procedure:
Potassium-benzylpenicillin (2.73 g., 0.00734 mole) was stirred in dry D.M.F. (100 ml.) with 3-bromo-5,6-dimethoxyphthalide (2.0 g., 0.00734 mole) for 12 hours. The mixture was poured into iced water (2 lits) with vigorous stirring and the solid filtered, dried and crystallised from isopropanol.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:30](O)([C:32]([F:35])(F)F)=O>C(Cl)Cl>[CH2:26]([NH:25][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([NH:11][C:14]3[CH:23]=[CH:30][C:32]([F:35])=[CH:16][CH:15]=3)=[O:5])[CH2:13][CH2:12]2)[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-2-(n-butylamino)-7-chloroquinoline (47 mg, 0.11 mmol) is deprotected with TFA in CH2Cl2 and transformed into the title product according to method C using 4-fluorophenyl isocyanate (18 μL, 0.16 mmol) and triethylamine (110 μL, 0.79 mmol) to give a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:34])=[N:31][C:32]=1[CH3:33])#[CH:26].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH2:34])=[N:31][C:32]=3[CH3:33])[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a mixture of 4-benzyloxy-phenyl-acetohydroximoyl chloride (59 mg, 0.21 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (1 mL) were added 5-ethynyl-6-methyl-pyridin-2-ylamine (22 mg, 0.16 mmol) described in Manufacturing Example 187-1-2 and triethylamine (46 μL, 0.33 mmol), which was stirred for 2 hours at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (35 mg, 57%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[C:7][CH2:8][OH:9])=[CH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([O:9][CH2:8][C:7]#[C:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OCC#Cc1ccoc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCC#Cc1ccoc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 3-(3-furyl)-2-propynyl alcohol (1.45 g, 0.0118 mol), DMAP (1 mg), TEA (2.46 ml, 0.017 mol), and acetic anhydride (1.6 ml, 0.017 mol) in 25 ml of methylene chloride was stirred for 1 hour and the mixture was poured into cold 1N HCl solution. The mixture was extracted with ether (3×50 ml), the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (hexane/ether, 2:1) to afford 1.44 g (57.5%) of 3-(3-acetyloxy-1-propynyl)furan as a clear oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:17][C:10]=23)O1.Br[C:43]1[CH:44]=[CH:45][C:46]([C:49]([NH:51][CH3:52])=[O:50])=[N:47][CH:48]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:52][NH:51][C:49]([C:46]1[N:47]=[CH:48][C:43]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:17][C:10]=23)=[CH:44][CH:45]=1)=[O:50]
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: CNC(=O)c1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 80 °C

Procedure:
A mixture of Example 369D (1.700 g, 2.93 mmol), 5-bromo-N-methylpicolinamide (0.757 g, 3.52 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.096 g, 0.117 mmol), and saturated sodium bicarbonate solution (10 mL, 2.93 mmol) in N,N-dimethylformamide (40 mL) was degassed and heated at 80° C. for 2 hours. The reaction mixture was filtered, treated with water and brine and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered, concentrated, and purified on an 80 g silica column using the ISCO Companion flash system eluting with heptanes/ethyl acetate (3:7 to 2:8) to give the title compound. MS (ESI+) m/z 588.1 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][N:20]=[C:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)(=O)C>[C:1]1([N:7]2[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][N:20]=[C:8]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2cccnc2N(c2ccccc2)C2=NCCN12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1C2=C(NCCC2)N(c2ccccc2)C2=NCCN12

Procedure:
Hydrogenate a mixture of 10% Pd/C (2.5 g), 10-phenyl-2,3-dihydroimidazo[1,2-a]pyrido[2,3-d]pyrimidin-5(10H)-one (5 g) and glacial acetic acid (125 ml) at 60 psi in a Paar apparatus for 24 hrs. at 25° C. Filter the mixture and evaporate the solvent of the filtrate. Dissolve the residue in 1N NaHCO3 (50 ml), neutralize with additional solid NaHCO3 and extract with CHCl3. Wash combined extracts with H2O, dry and filter. Evaporate solvent of the filtrate and crystallize the residue from EtOAc--MeOH to give 10-phenyl-2,3,6,7,8,9-hexahydroimidazo[1,2-a]-pyrido[2,3-d]pyrimidin-5(10H)-one, m.p. 248.0°-250.5° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][CH:3]=1.[I:11]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(O)(=O)C>[I:11][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(=O)c(C#N)cc1I
Yield: 85.8 %

Procedure:
A mixture of 13.4 g (0.1 mole) of 1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 22.5 g (0.1 mole) of N-iodosuccinimide and 5 mL of trifluoroacetic acid in 250 mL of acetic acid was heated to reflux under argon for 4 hrs. The reaction was cooled and filtered to remove the crystalline precipitated product which was washed with water and ether and air dried to give 22.3 g (86%) of the 5-iodopyridinone as dense, light yellow needles, mp 260-264.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(S(F)(F)[F:62])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:62])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 64 yields 17-ethyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.S(Cl)([Cl:21])=O>>[Cl:21][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2oc(S)nc2c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2oc(Cl)nc2c1
Temperature: 65 °C

Procedure:
Subsequently, the crude 2-mercapto-5-nitrobenzoxazole (10 g, 51 mmol), previously prepared, was dissolved in thionyl chloride (100 mL). DMF (60 μL) was added and the reaction mixture was heated at 65° C. for 45 min. After cooling, the solvent was removed under reduced pressure and to the residue, toluene was added twice (2×20 mL) and each time subsequently evaporated in vacuo to remove volatiles via azeotrope. The resultant crude product was dissolved in ethyl acetate (400 mL), washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give compound 29, 2-chloro-5-nitrobenzoxazole, as (8.2 g, crude).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[OH:9][C@:10]([CH3:46])([CH2:44][OH:45])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([S:5]([O:45][CH2:44][C@:10]([OH:9])([CH3:46])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: CCCCS(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COC)NC(=O)[C@H](COC)NC(=O)c1cnc(C)s1

Procedure:
Prepared according to procedures described above, by reacting butanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C29H42N4O10S2 m/z: 671 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OCCN1CCOCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(OCCN2CCOCC2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, N-(2-hydroxyethyl)morpholine and DBU in THF. ES-MS m/e (%): 417 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=4[F:37])=[O:28])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C.Br[CH2:48][C:49]([O:51][CH3:52])=[O:50].O>CN(C=O)C>[F:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:11]3[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:7])[CH:12]=3)[CH:18]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)cc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNCCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (260 mg, 0.52 mmol) and N,N-diisopropylethylamine (134 mg, 1.04 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (80 mg, 0.52 mmol). The mixture was stirred at room temperature for 40 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜10% MeOH/CHCl3 to afford methyl [(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)amino]acetate as white solid. Yield: 100 mg, 34%.
Reaction SMILES: C([C:8]1[NH:12][C:11]([C:13]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([CH:26]=[O:27])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH3:17])=[O:14])=[CH:10][CH:9]=1)C1C=CC=CC=1.C(C1NC(C(N[C@@H](C(N[C@H]2CC(=O)O[C@@H]2OCC2C=CC=CC=2)=O)C)=O)=CC=1)C1C=CC=CC=1.CO.[K+].[Br-]>O>[NH:12]1[CH:8]=[CH:9][CH:10]=[C:11]1[C:13]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([CH:26]=[O:27])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH3:17])=[O:14]
Reactant: C[C@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)N[C@H](C=O)CC(=O)O
Agent: C[C@@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)c1ccc[nH]1)C(=O)N[C@H](C=O)CC(=O)O

Procedure:
(3S)3-[N-(5-Benzylpyrrole-2-carbonyl)-L-alaninyl]amino-4-oxobutanoic acid (36b), was prepared (41%) from 35b by the method described for compound 36a, to afford an off white solid: mp. 109°-112° C.; [α]D25 +6.3° (c 0.3, methanol); IR (KBr) 3368, 1724, 1630, 1530, 1453, 1414, 1233, 1049; 1H NMR(d4 methanol) δ 7.25-7.11 (5H, m), 6.76 (1H, d, J=3.5), 5.84 (1H, d, J=3.5), 4.51 (1H, m), 4.43 (1H, q, J=7.1), 4.23 (1H, m), 2.5 (2H, m),1.35 (3H, d, J=7.0). Anal. Calcd for C19H21N3O5. 1.75 H2O: C, 56.64; H, 6.13; N, 10.43. Found: C, 56.34; H, 5.72; N, 10.00. ##STR120##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]>CN(C(OC)OC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[C:10]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])=[CH:10][N:11]([CH3:19])[CH3:12]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O

Procedure:
1 mmol of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione was heated to 80° C. in N,N-dimethylformamidedimethyl acetal for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether.