Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C(OCC)C>C(Cl)Cl>[O:21]=[C:18]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH3:2])=[O:10])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1CCCC1C(=O)OC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
L-Proline methyl ester hydrochloride (8.27 g, 0.05 mole) was dissolved in 250 ml of methylene chloride and triethylamine (40 ml, 0.28 mole) added thereto. The solution was filtered to remove the precipitate and cooled to 5° C. Over a period of 30 minutes, a solution of acryloyl chloride (4.52 g, 0.05 mole) was added to the cooled solution, the reaction allowed to warm to room temperature and stirred for 12 hours. Ethyl ether (100 ml) was then added to the solution and the resulting white solid filtered. An additional 200 ml of ethyl ether was added and a small amount of tan solid filtered out. The solvents were evaporated, and the resulting oil chromatographed on silica to isolate the product. The product was dried in vacuo at room temperature for 72 hours. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=S)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].[NH2:25][NH2:26]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=[N:25][NH2:26])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=S)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Reactant: NN
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cc(C(=NN)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of 4-(2,3-difluoro-phenylthiocarbamoyl)-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (420 mg, 1.12 mmol) in CH2Cl2 (5 mL) and EtOH (5 mL) was added NH2NH2 (50 mg, 1.56 mmol) at room temperature. The mixture was stirred for 3 hours and the solvents were removed by evaporation under reduced pressure. The crude yellow solid product (410 mg, 98%) was dried on the pump for direct use. MS (ES+): m/e=373.1 (M+H); LC/Method A/2.70 min.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH3:16])=[O:14])[C:9]([Cl:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(ON=O)CC(C)C>C1COCC1>[Cl:12][C:11]1[CH:2]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[C:9]([Cl:17])[C:10]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a solution of dimethyl 2-amino-3,5-dichloroterephthalate (200 g, 0.72 mol) in THF (1 L) at room temperature was slowly added isoamylnitrite (240 mL). The mixture was heated under reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum-diethyl:ether (50:1) to give dimethyl 2,6-dichloroterephthalate (187 g, yield: 98%) as a light yellow solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH3:11])=[N:9][N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[SH-:17].[Na+].Cl>O>[CH2:15]([O:14][C:12]([C:4]1[CH:3]=[C:2]([SH:17])[N:7]2[C:8]([CH3:11])=[N:9][N:10]=[C:6]2[N:5]=1)=[O:13])[CH3:16]
Reactant: [SH-]
Reactant: CCOC(=O)c1cc(Cl)n2c(C)nnc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2c(C)nnc2n1
Yield: 80.8 %

Procedure:
The product obtained in Step 2 (4.0 g) was added all at once under ice cooling to a solution of 4.0 g of sodium hydrosulfide in 100 ml of water with stirring in nitrogen, and the mixture was stirred at room temperature overnight. The resulting solution was acidified to pH 1.0 with 6N hydrochloric acid, and the separated crystals were collected by filtration and recrystallized from ethanol, affording 3.2 g of the objective compound as orange crystals.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16]CC4C=CC(OC)=CC=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.C(O)(C(F)(F)F)=O>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH2:16])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(N)s4)ccc32)cc1

Procedure:
A solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (0.50 g, 0.811 mmol) and TFA (2.0 mL, 26.9 mmol) was heated in a microwave at 100° C. for 8 min. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with sat. NaHCO3. The organic layer was dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 497 (M+1).
Reaction SMILES: O1[C:3]23[C@H:16]([CH2:17][CH2:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@:7]24[CH2:22][C@H:8]2[CH2:9][C@H:10]([OH:21])[C@:11]4([CH2:13][CH2:14]1)[CH3:12])[CH2:5][CH2:4]3.[ClH:23].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:23][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@H:16]2[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@@:7]31[CH2:22][C@H:8]3[CH2:9][C@@H:10]2[OH:21]
Reactant: Cl
Reactant: C[C@]12CC[C@@H]3[C@H]4CCC(=O)C5OC54CC[C@H]3[C@@]13C[C@H]3C[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(Cl)C(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O

Procedure:
The epoxide mixture of step 1 (2 g) is dissolved in 200 ml of acetone and treated at 5° C. with 12 ml of concentrated hydrochloric acid. After 2 house, the mixture is neutralized with sodium carbonate solution and the acetone is removed. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated, After crystallization from ethanol, 4-chloro-17β-hydroxy-14α,15α-methylenestr-4-ene-3-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][N:31]([CH2:35][CH2:36]O)[CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:36][CH2:35][N:31]([CH2:32][CH2:33][OH:34])[CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CN(CCO)CCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCO)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and N-methyldiethanolamine following General Procedure K.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH:29][CH3:30])[CH3:28]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([N:29]([CH2:27][CH3:28])[CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CCNC
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: CCN(C)C(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.10 g, 2.8 mmol) in CH2Cl2 (10 mL) was added neat ethyl(methyl)amine (310 μL, 3.6 mmol) dropwise. The mixture was stirred at room temperature for 1 h. Solvents were removed by concentration. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-ethyl-3-methylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (1.09 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 1.15 (t, 3H, J=7.0 Hz), 2.05 (s, 3H), 2.06 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3H), 3.08 (s, 3H), 3.74-3.81 (m, 3H), 4.16 (dd, 1H, J=2.0, 12.5 Hz), 4.27 (dd, 11, J=4.5, 12.5 Hz), 5.14 (t, 1H, J=10.0 Hz), 5.26 (t, 1H, J=10.0 Hz), 5.34-5.40 (m, 2H), 5.78 (d, 1H, J=8.0 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=1
Reactant: C#CCO
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ccccc2)nc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 304 mg of 4-chloro-2-methyl-6-phenylpyrimidine and 92 mg of 2-propyn-1-ol, to which 66 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 256 mg of 2-methyl-4-phenyl-6-(2-propynyloxy)pyrimidine (the present compound (77)).
Reaction SMILES: I[Si](C)(C)C.[NH2:6][C:7]1[C:8]([C:15](/[N:17]=[C:18]2\[NH:19][CH2:20][C:21]3([CH2:28][CH:27]4[N:29](C(OC(C)(C)C)=O)[CH:24]([CH2:25][CH2:26]4)[CH2:23]3)[NH:22]\2)=[O:16])=[N:9][C:10]([Cl:14])=[C:11]([NH2:13])[N:12]=1.CN(C=O)C>C(Cl)Cl>[NH2:6][C:7]1[C:8]([C:15](/[N:17]=[C:18]2\[NH:19][CH2:20][C:21]3([CH2:28][CH:27]4[NH:29][CH:24]([CH2:25][CH2:26]4)[CH2:23]3)[NH:22]\2)=[O:16])=[N:9][C:10]([Cl:14])=[C:11]([NH2:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC1(CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N1)C2
Agent: C[Si](C)(C)I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodotrimethylsilane (0.23 ml, 1.66 mmol) is added to a suspension of (E)-tert-Butyl 2′-(3,5-diamino-6-chloropyrazine-2-carbonylimino)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-8-carboxylate (Ex. 251) (500 mg, 1.11 mmol) in DCM (10 ml). DMF (5 ml) is then added and the reaction is stirred at room temperature overnight. Iodotrimethylsilane (0.5 ml) is added and the reaction mixture is concentrated in vacuo. The yellow solid is suspended in DCM and collected by filtration. The solid is dissolved in 1:1 MeOH/DCM and loaded onto an SCX-2 cartridge eluted with DCM followed by MeOH and NH3/MeOH. The methanolic ammonia fractions are concentrated in vacuo to afford (E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide as a yellow gum; [M+H]+ 351
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.C([Li])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[CH3:21][O:20][C:18](=[O:19])[C:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: Fc1cccc(C=C(Br)Br)c1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cccc(F)c1
Yield: 110.3 %

Procedure:
To a stirred solution of 1-(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8 g) in anhydrous THF (350 ml) cooled to −78° was added dropwise over 30 minutes, n-butyllithium (2.2 eq, 1.6M in hexanes). The mixture was stirred for a further 30 minutes at −78° before methyl chloroformate (11.6 g, 9.5 ml) was added and the resultant mixture allowed to warm to 0° for 1hour before being diluted with 1:1saturated aqueous sodium bicarbonate:ammonium chloride (100 ml) and extracted into ether (2×100 ml). The combined organic extract was washed with brine (25 ml), dried (Na2SO4) and evaporated to dryness to give the title compound as a brown oil (16.7 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>C(O)CCC>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][N:26]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])=[CH:21][CH:20]=1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCC(C(=NNc2ccc(F)cc2)c2ccccc2F)CC1
Yield: 23.1 %

Procedure:
A stirred mixture of 21.8 g of 4-(2-fluorobenzoyl)-1-methylpiperidine, 20.25 g of 4-fluorophenyl hydrazine hydrochloride and 25.0 g of sodium acetate in 420 ml of n-butanol was heated under reflux for 8 hrs. The mixture was cooled, filtered, and concentrated. The residue was washed with ether to give 7.5 g (23%) of 4-(2-fluorobenzoyl)-1-methylpiperidine 4-fluorophenylhydrazone, mp 125°-126° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(OCC)C>CN(C)C=O.O>[CH2:14]([O:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH:16]1[O:18][CH2:17]1
Reactant: Oc1cccc2ccccc12
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(OCC3CO3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (4.0 g of 60% NaH in mineral oil, 100 mmol) in dimethylformamide (DMF, 100 ml) was treated with 1-naphthol (14.42 g, 100 mmol). After stirring for 1 hour at ambient temperature (room temperature), the reaction was treated with epichlorohydrin (10.18 g, 110 mmol) and stirred for 1 hour at 100° C. The reaction was diluted with water and transferred to a separatory funnel using diethyl ether (500 ml). The organic phase was washed with 10% aqueous NaHCO3 (3×200 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. Kugelrohr distillation (˜100 microns) yielded 1-naphthyl glycidyl ether as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 200 (M+, 61), 184 (1), 169 (5), 157 (12), 144 (79), 129 (16), 115 (100), 101 (3), 89 (16).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:6]=1[CH:7]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)O.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH:7]([C:6]1[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:3][C:2]=1[CH3:1])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Cc1oc(-c2ccccc2)cc1C(O)C1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (2-methyl-5-phenylfuran-3-yl) (tetrahydro-2H-pyran-4-yl)methanol (1.8 g) in toluene (20 mL) was added thionyl chloride (1.4 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.9 g, 100%) as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(=O)=O>C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:43]
Reactant: CCOC(=O)CCCCCOS(C)(=O)=O
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the non-polydispersed alcohol 16 (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0° C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The non-polydispersed mesylate 17 (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the non-polydispersed product as a pale yellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH2:14][C:15](=[O:18])[NH:16][N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>C(#N)C>[CH3:24][N:25]([CH:27]=[C:14]1[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:17][NH:16][C:15]1=[O:18])[CH3:26]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(C2=NNC(=O)C2)cc(OC)c1OC
Solvent: CC#N
Product: COc1cc(C2=NNC(=O)C2=CN(C)C)cc(OC)c1OC
Temperature: 35 °C
Reaction time: 36 h

Procedure:
5-(3,4,5-Trimethoxyphenyl)-2,4-dihydro-pyrazol-3-one (k, 2 g) in dry actonitrile (10 mL) was added C-tert-Butoxy-N,N,N′,N′-tetramethyl-methanediamine (3 mL) and stirred at 35° C. The reaction was monitored by HPLC. After 36 hours, the solid was filtered and rinsed with dry acetonitrile (5 mL) and dried under nitrogen pressure to yield the title compound (1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH3:20][N:21]1[C:25]([CH:26]=O)=[CH:24][CH:23]([CH3:28])[NH:22]1.C([BH3-])#N.[Na+].C1COCC1>O.C(O)(=O)C>[CH3:20][N:21]1[C:25]([CH2:26][NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[C:5]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)=[O:6])=[CH:24][C:23]([CH3:28])=[N:22]1
Reactant: CC1C=C(C=O)N(C)N1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A dry round bottom flask was charged with 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.300 g, 1.19 mmol), 1,3-Dimethyl-2H-pyrazole-5-carbaldehyde (0.191 g, 1.91 mmol) and acetic acid (0.3 mL). The mixture was allowed to stir for 4 h at room temperature. A 1M solution of sodium cyanoborohydride in THF (3.57 mL, 3.57 mmol) was then added and the mixture was allowed to stir for 45 minutes. The reaction mixture was poured into H2O (100 mL) and allowed to stir for 15 minutes. The resulting suspension was vacuum filtered and the filtrate was extracted with EtOAc (3×˜100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a yellow oil. The yellow oil was then chromatographed over silica which had been previously neutralized by flushing the column with the purification eluant (97/3, chloroform/methanol w/0.5% NEt3) several times. This chromatographic purification resulted in the isolation of pure 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-1,3-dihydro-indol-2-one in 30% yield (0.128 g, 0.357 mmol).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>C1COCC1>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:19](=[O:20])[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:21])=[CH:13][CH:14]=1)[C:1]#[N:2]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
The anion of methyl cyanoacetate (2.20 g, 22.2 mmoles) was made at 0° C. using sodium hydride (0.8 g, 22 mmoles) in 70 ml of THF and treated dropwise with 4-trifluoromethylphenyl isocyanate (4.1 g, 22 mmoles). After one hour at 0° C. the solvent was removed and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, dried and partially concentrated in vacuo to precipitate the title compound (3.8 g) as a white solid, mp 186°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11]>O1CCOCC1>[CH2:10]([O:12][C:13]([NH:15][C:16]([NH2:7])=[S:17])=[O:14])[CH3:11].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: CCOC(=O)N=C=S
Agent: COc1ccc(N)nc1
Solvent: C1COCCO1
Product: CCOC(=O)NC(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 201.5 %

Procedure:
To 5-methoxypyridin-2-amine (5 g, 40 mmol) in dioxane (40 mL) was added ethoxycarbonyl isothiocyanate (5.23 mL, 44.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to afford 5-methoxypyridin-2-amine ethoxycarbonyl thiourea (10.28 g, 40.3 mmol, 100% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.03 (1 H, br. s.), 11.37 (1 H, br. s.), 8.53 (1 H, br. s.), 8.11 (1 H, d, J=2.93 Hz), 7.50 (1 H, dd, J=8.97, 3.11 Hz), 4.22 (2 H, q, J=7.07 Hz), 3.84 (3 H, s), 1.26 (3 H, t, J=7.14 Hz). MS (LC/MS) R.T.=2.40; [M+H]+=256.1.