Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH:22]=[CH:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>CN(C)C=O.O>[C:31]1([C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:32]=[N:14][N:15]2[CH:20]=[CH:19][C:18]3[O:21][CH:22]=[CH:23][C:17]=3[C:16]=12
Reactant: N[n+]1ccc2occc2c1
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc3occc3c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a mixture of 5-aminofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.14 mmol) and potassium carbonate (608 mg, 4.40 mmol) in dimethylformamide (20 mL) was added ethyl propiolate (350 μL, 3.45 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→440/60) to give the title compound (451 mg, yield 62%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[C:23]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2cccc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 6.5 mL of 3-chlorobenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 122°-124° C.). 1H NMR (CDCl3) δ 2.83 (dd, 1 H), 2.96 (dd, 1 H), 3.60 (dd, 2 H), 5.68 .(dd, 1 H), 7.25-7.42 (m, 4 H).
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(=O)([O-])N.[CH2:16]([NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](N4CCC(N5CCCC5)CC4)=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])[CH3:17]>C(OCC)C>[CH2:16]([NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([N:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])[CH3:17]
Reactant: C1COCCN1
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Agent: NC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and morpholine (0.326 ml, 3.73 mmol) were added to a mixture (0.401 g) of phenyl N-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the obtained solid was washed with a solvent mixture of hexane:diethyl ether=1:1 to yield the title compound (255 mg, 0.62 mmol).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH2:45][CH2:46][CH:47]=O)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>C1COCC1>[CH3:2][O:3][CH:4]=[CH:47][CH2:46][CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]2)[CH2:40][CH2:41]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=COC)CC2)CC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A mixture of 57.3 g (167 mmol) of methoxymethyl-triphenylphosphonium chloride and 500 ml of THF was cooled to −30° C. under a nitrogen gas stream with a refrigeration medium. 17.3 g (154 mmol) of t-BuOK was added to this mixture, followed by stirring for 1 hour. To this mixture, 300 ml of THF containing 34.0 g (129 mmol) of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propanal was added dropwise, while a temperature of −30° C. or less was maintained. After the dropping, a reaction temperature was gradually raised to room temperature, followed by stirring for 5 hours. The reaction mixture was filtered through Celite, and the solvent was then distilled off under reduced pressure. The resulting residue was purified through silica gel column chromatography (a developing solvent: heptane) to obtain 30.3 g of crude 1-methoxy-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:12]=1)[CH2:7][NH:8][C:9](=[O:11])[CH3:10].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>O1CCCC1.[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:12][C:6]=1[CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)NCc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Combine N-(5-bromo-2-fluorobenzyl)acetamide, (prepared as described in PREPARATION 30), (370 mg, 1.50 mmol, zinc(II) bromide (588 mg, 2.25 mmol), and triethylamine (1.00 mL, 7.20 mmol) in tetrahydrofuran (3.7 mL). After stirring for 5 min, add trimethylsilylacetylene (0.53 mL, 3.76 mmol) and tetrakis(triphenylphosphine)palladium (0) (87 mg, 0.075 mmol). Heat the mixture in a sealed tube at 60° C. overnight. Cool the reaction to room temperature and filter through diatomaceous earth. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with a gradient from 75:25 to 65:35 with a solution of (1:1 hexanes and dichloromethane):ethyl acetate to give the title compound as a yellow oil which crystallizes upon standing (309 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]I)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(CCI)coc12
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc12

Procedure:
A mixture of 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored low melting solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetae:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a dark brown low melting solid. Yield: (HCl salt) 90 mg (21%); (M+H): 388; 1H NMR: δ□11.9 (bs, 1H), 9.2 (d, 1H), 9.0 (bs 1H), 8.2 (m, 2H), 7.9 (s1H), 7.84 (m, 2H), 7.45 (d, 1H), 7.21 (t, 1H), 6.98 (d, 1H), 4.01 9s, 3H), 3.77 (m, 4H), 3.67 9m, 2H), 3.59 (m, 4H), 3.3 (m, 2H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20](F)=[N:21][CH:22]=1.Cl>CS(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20]([O:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[N:21][CH:22]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Reactant: Fc1cc(Br)cnc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ncc(Br)cc2F)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
A solution of NaOH (0.54 g, 0.013 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (1.22 g, 0.0067 mol) in 20 ml DMSO and the mixture was stirred for 20 minutes under N2. 5-Bromo-2,3-difluoropyridine (1.3 g, 0.0067 mol) was added and the mixture was stirred for 51/2 hours at 80°-90° C. The reaction mixture was poured into water, acidified with concentrated HCl to pH 1 and extracted into CH2Cl2. The solution was dried over Na2SO4 and the solvent was removed by rotary evaporation to yield a gum which became an off-white solid (0.78 g, 33%, m.p. 94°-97° C.) upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:32][C:33]([NH2:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])([CH3:35])([CH3:34])[CH3:32]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
The mixture of 2-chlorobenzoic acid (20 g, 128 mmol), HOBT (34.6 g, 256 mmol), EDCI (48.8 g, 256 mmol), 2-methylpropan-2-amine (9.3 g, 128 mmol) and TEA (25.9 g, 256 mmol) in THF (600 mL) was stirred at room temperature overnight. After solvent evaporation, the mixture was diluted with ethyl acetate (600 mL) and washed with water (3×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/PE (1:5) to give the title product as a white solid (23.9 g, yield: 88.5%). LC-MS: m/e=212 (M+H)+; Rt=0.85 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:20][CH3:21])(=O)=O>CC(=O)CC.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:20][CH3:21])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: Oc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOc1cc(Br)cc(Br)c1
Temperature: 90 °C

Procedure:
A dispersion of 3,5-dibromophenol (0.398 g, 1.6 mmol) and potassium carbonate (0.437 g, 3.2 mmol) in 2-butanone (4 mL) was treated with diethyl sulfate (0.246 g, 1.6 mmol) and the reaction mixture heated at 90° C. for 15 hours. The resulting thick suspension was cooled to room temperature, diluted with dichloromethane and extracted with water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The title compound was obtained as a light brown oil (0.38 g, 86% of theory) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](NCCCC)[N:7]=2)[CH2:3]1.C(OC(=O)NC1CN(C2C=CN=C([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])N=2)C1)(C)(C)C.Cl.CO>C(O)=O>[NH2:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:38][CH2:37][CH2:36][CH2:35][NH2:34])[N:7]=2)[CH2:5]1
Reactant: CCCCNc1nccc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Reactant: CCCCNc1nccc(N2CC(N)C2)n1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: NCCCCc1nccc(N2CC(N)C2)n1
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 98 %

Procedure:
[1-(2-Chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester To a flask containing 2,4-dichloropyrimidine (1.6 g, 10.7 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) in i-PrOH (40 mL) was added azetidin-3-yl-carbamic acid tert-butyl ester monohydrochloride (2.1 g. 12.2 mmol). The reaction mixture was heated to 70° C. for 72 h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by flash chromatography on SiO2 (100% hexane increasing gradient to 60% EtOAc-Hexane) to yield two isomeric products. The minor upper Rf product was obtained as a white solid (326 mg, 11%), and the desired major lower Rf product was also obtained as a white solid (2.1 g, 69%). [1-(2-Butylamino-pyrimidin-4-yl)azetidin-3-yl]-carbamic acid tert-butyl ester. To a solution of [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in i-PrOH (3.0 mL) was added butylamine (600 μL, 6.0 mmol). The reaction mixture was heated to 95° C. in a sealed tube for 36-48 h followed by cooling to room temperature. The reaction mixture was then concentrated and the crude residue purified by flash chromatography on SiO2 using (100% EtOAc increasing the gradient gradually to 5% 2M NH3-MeOH) to yield the desired product (260 mg, 92%). [4-(3-Amino-azetidin-1-yl)-pyrimidin-2-yl]-butyl-amine. To a solution of [1-(2-butylamino-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in formic acid (4 mL) was added 6N HCl (300 μL). The reaction mixture was stirred at room temperature for 15-30 minutes. Then, MeOH (10 mL) was added and stirred for 10 minutes. The contents were then concentrated and the crude residue purified by flash chromatography on SiO2 using an increasing gradient of (0 to 10% NH3/MeOH in CH2Cl2) to yield the desired product (225 mg, 98%) as the free base. MS (ESI): mass calcd. for C11H19N5, 221.3 m/z found, 222.2 [M+H]+. 1H NMR (CD3OD): 7.61 (d, J=7.3, 1H), 5.99 (d, J=7.1, 1H), 4.6-4.7 (m, 2H), 4.28-4.48 (m, 3H), 3.40 (bs, 1H), 1.54-1.62 (m, 2H), 1.31-1.41 (m, 2H), 0.90 (t, J=7.4, 3H). The compounds in Example 85 through Example 94 were prepared using methods analogous to those described for Example 84.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][C@H:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[C@H:3]2[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
To a stirred solution of 5,6-dihydro-2H-pyran-2-one* (136 g, 1.39 mole) in dichloromethane (2 L) at -20° C. was added N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethyl amine (80% pure) (D12, 450 g, 1.5 mole). To this solution was added trifluoroacetic acid in dichloromethane (140 ml, 1 molar solution) at -20° C. The reaction was then transferred at -20° C. under a small positive pressure of nitrogen via a double ended needle to a second flask on a water bath at 30° C. As the cold mixture warmed up an exothermic reaction occurred and the rate of addition was controlled to maintain gentle reflux. When addition was complete and the reaction had subsided the solution was allowed to stand at room temperature for 2 h. The reaction was then washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacuo to a gum. Vacuum distillation afforded the title compound as a single main fraction b.p. 180°-190° C. 0.5mmHg (D20, 180.9 g, 0.73 mole, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]=[CH:10][N:11](C)C)=O)[S:5][CH:6]=1.[CH3:14][NH:15]N>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[N:15]([CH3:14])[N:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: CN(C)C=NC(=O)c1cc(Cl)cs1
Reactant: CNN
Solvent: CC(=O)O
Product: Cn1ncnc1-c1cc(Cl)cs1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A 3-L reaction flask equipped with a cooling bath, air stirrer, and thermometer probe is charged with 4-chloro-N-dimethylaminomethylene-2-thiophene carboxamide. (155 g, 0.715 moles) and HOAc (1500 mL) to form a solution. Using an ice-water cooling bath to maintain the temperature at ≦30° C., methylhydrazine (33.2 g, 0.721 moles) is added dropwise via an addition funnel over 15-20 minutes to form a light yellow slurry. Gradually, the reaction is heated to 90° C. and held at 90° C. for 30 minutes. After analysis of the mixture by GC, the reaction is cooled to ˜70° C.; then, concentrated to a thick oil/slurry. De-ionized H2O (1.67 L) is slowly added to precipitate solids; then, the mixture is cooled to <30° C., filtered and washed with de-ionized H2O (1.67 L). The wet solids (125.8 g) are re-dissolved in warm MTBE (1.64 L), dried over Na2SO4, filtered and concentrated to dryness giving the title compound as a pale yellow solid (85.8 g, 60.1% 91.9% area % by GC).
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)C>[C:19]1([C:17]2[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccccc2)cs1
Yield: 75.4 %

Procedure:
To ethyl 2-amino-2-thioxoacetate (4 g, 30 mmol) in ethanol (50 mL) was added pyridine (0.24 g, 3 mmol). 2-Bromo-1-phenylethanone (5 g, 25 mmol) was added after 10 minutes and the mixture was then heated at reflux for 6 hours. The resulting mixture was washed with water and extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give a crude product, which was purified by column chromatography to afford the title compound as a white solid (4.4 g). MS (ESI) m/z 233 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:16]1(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[CH2:18][O:17]1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11](/[CH:14]=[C:18]3\[O:17][C:16](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19]\3=[O:26])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: O=C1COC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1O/C(=C\[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To the resulting stirred mixture from stage 1, at ambient temperature under argon, was added acetic acid (125 mL), 1H-2-benzopyran-1,4(3H)-dione (compound of formula (III)) (16.2 g, 100 mmol) and ammonium acetate (7.7 g, 100 mmol). The reaction mixture was then heated to 70° C. and distilled for 2 hours. The resulting slurry was cooled to ambient temperature and water (75 mL) added. The slurry was stirred for 30 minutes at ambient temperature then filtered. The filter cake was washed with tert-butyl methyl ether (62.5 mL) and dried to give the title compound as a yellow solid (24.8 g). The material obtained was spectroscopically identical to that obtained in Stage 2, Example 3.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:13][C:14](=[O:25])[CH2:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH2:15][C:14]([NH:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:25])=[S:4]
Reactant: NNC(N)=S
Reactant: O=C(CCC(=O)c1ccccc1)NCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCC(=O)NCc1ccccc1)c1ccccc1
Yield: 87.9 %

Procedure:
Thiosemicarbazide (2.30 g, 25.2 mmol) was added to a solution of N-benzyl-4-oxo-4-phenyl-butyramide (4.12 g, 15.4 mmol), prepared in the previous step, in 100 ml of methanol plus 4.2 ml of 1 N HCl plus 4.2 ml of water and the reaction stirred at room temperature for 20 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried to give 4.61 g of a white solid. Recrystallization of the solid from ethyl acetate-methanol gave the title compound (2.05 g, 39%) as a white solid, mp 162-164° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30](CC[Si](C)(C)C)[C:29](=[O:40])[CH2:28]1)C1C=CC=CC=1.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([S:47]([N:18]2[C@H:17]([CH2:16][CH2:15][C:13]3[CH:12]=[CH:11][C:10]([N:27]4[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:40])[CH2:28]4)=[C:9]([OH:8])[CH:14]=3)[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(CC[C@@H]3Cc4ccccc4CN3S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-{2-benzyloxy-4-[(E)-(S)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and benzenesulfonyl chloride analogous to Example 200, steps F, G and H: LC retention time=1.26 min (Method A); (M+NH4)+=545.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([CH:30]1[CH2:32][CH2:31]1)[NH2:29]>>[CH:30]1([C:28]2[N:29]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][S:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:27]=2)[CH2:32][CH2:31]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: NC(=NO)C1CC1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 91 mg (0.91 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 141 mg (40% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[N:8][N:9]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:30])[F:31])[CH:22]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 53.8 %

Procedure:
A blue-green suspension of 5-methyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 3.03 mmol), molecular sieves 4A, 3-(trifluoromethoxy)benzeneboronic acid (1.25 g, 6.05 mmol), copper (II) acetate (824 mg, 4.54 mmol) and pyridine (0.48 ml, 6.05 mmol) in 14 ml CH2Cl2 was stirred under argon atmosphere and at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The aqueous phases were extracted twice with CH2Cl2, the combined organic layers dried over magnesium sulfate, and evaporated. The residue was treated with EtOAc:toluene, 1:9, filtered off. The filtrate was evaporated and chromatographed twice (amino-phase silica gel, toluene:EtOAc 9:1) to afford the title compound as a colorless oil (638 mg, 54%). MS: 392.1 (MH+).