Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:19]2[CH2:18][C@H:17]3[N:20]([CH2:22][CH2:23][C@@:9]45[C@H:16]3[CH:15]=[CH:14][C@H:12]([OH:13])[C@@H:10]4[O:11][C:7]([C:8]=25)=[C:5]([OH:6])[CH:4]=1)[CH3:21].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].II>O.CO>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:6][C:5]2[CH:4]=[CH:3][C:19]3[CH2:18][C@H:17]4[N:20]([CH3:21])[CH2:22][CH2:23][C@:9]56[C:8]=3[C:7]=2[O:11][C@H:10]5[C@@H:12]([OH:13])[CH:14]=[CH:15][C@@H:16]46)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.5 g (37.5 mmol) of NaH (60% dispersion in mineral oil) was rinsed with 2×25 mL of hexanes to remove the oil. To the reaction mixture was added 140 mL of anhydrous DMF followed by 10.1 g (35 mmol) of morphine. This mixture was allowed to stir at room temperature for 30 minutes under nitrogen atmosphere, and 14.5 g (53 mmol) of N-(3-bromopropyl) phthalimide was added. The reaction mixture was allowed to stir 18 h at room temperature. The reaction was monitored by thin layer chromatography (silica, 7:2:1:1, MeOH:EtAc:NH40H:H2O, I2 visualization), which showed that the reaction was incomplete. To the reaction mixture 0.15 g (3.75 mmol) of NaH (60% in oil) was added, and the mixture was allowed to stir for an additional 1.5 h. The mixture was poured into 350 mL of ice-water and extracted with 250 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2×250 mL of ethyl acetate. The organic layers were combined and washed with 2×150 mL of water, 150 mL of 1N NaOH and 2×150 mL of water. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized with diethyl ether to give 12.9 g (27.3 mmol, 77%) of the desired product 13 as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].O1CCCCC1[N:36]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[N:37]1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:38]3[NH:37][N:36]=[CH:40][CH:39]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 10 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 14.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a pale yellow powder. UPLC-MS (Condition 3) tR=0.96 min, m/z=466.2 [M+H]+, m/z=464.2 [M−H]−. 1H-NMR (400 MHz, DMSO-d6) d ppm 2.77 (s, 3H) 3.38-3.61 (m, 4H) 4.61 (br. s, 1H) 6.47 (s, 1H) 7.68 (d, J=8.56 Hz, 2H) 7.83 (br. s, 1H) 7.93 (d, J=8.80 Hz, 2H) 8.15 (br. s, 1H) 8.71 (br. s, 1H) 10.36 (s, 1H) 12.83-13.15 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=O)=O.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:4]([CH2:3][O:2][CH3:1])=[C:6]2[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH2:11]2)#[N:15]
Reactant: COCC(=O)C1CC(C)CCC1=O
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COCc1[nH]c(=O)c(C#N)c2c1CC(C)CC2

Procedure:
Crude 2-methoxyacetyl-4-methylcyclohexanone, 3.7 g, 1.68 g of cyanoacetamide and 1 ml of piperidine were mixed with 50 ml of ethanol followed by heating to reflux for 4 hours. The precipitated crystals were taken out by filtration and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl7-methyl-3-oxoisoquinoline.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][NH2:9].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=O>C1(C)C=CC=CC=1>[CH3:19][C:12]1([CH3:18])[NH:10][CH2:7][CH2:8][NH:9][C:13]1=[O:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)NCCNC1=O

Procedure:
Potassium carbonate (390 grams) and ethylene diamine (1001 grams) are stirred with toluene (1.50 l). A solution of ethyl 2-bromoisobutyrate (500 grams) in toluene (750 ml) is added. The suspension is heated to reflux over night, and filtered. The filter cake is washed with toluene (500 ml). The combined filtrates (volume 4.0 l) are heated on a water bath and distilled at 0.3 atm. using a Claisen apparatus; first 1200 ml distillate is collected at 35° C. (the temperature in the mixture is 75° C.). More toluene is added (600 ml), and another 1200 ml distillate is collected at 76° C. (the temperature in the mixture is 80° C.). Toluene (750 ml) is added again, and 1100 ml of distillate is collected at 66° C. (temperature in the mixture 71° C.). The mixture is stirred on an ice bath and inoculated, whereby the product precipitates. The product is isolated by filtration, washed with toluene, and dried over night in a vacuum oven at 50° C. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one. NMR consistent with structure.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:9]([F:24])[CH:8]=1.[C:25](=[O:27])=[O:26].Cl>C1COCC1.CCOCC>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:25]([OH:27])=[O:26])=[CH:8][C:9]=1[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C=O
Reactant: CCCCCCCCCCOc1ccc(Br)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1F

Procedure:
A solution of n-butyllithium was added dropwise to a stirred, cooled (-78° C.) solution of compound of step 2.1 in dry THF. The mixture was maintained under these conditions for 40 mins and then poured into a slurry of dry ether and cardice. The solution was acidified with 36% HCl, washed with water and dried (magnesium sulphate). The solvent was removed to yield a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:9](=[O:10])[C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]#[N:26])#[N:18]>ClC1C=CC=CC=1>[OH:10][C:9]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:21]2[C:22]=1[CH:23]=[C:24]([C:25]#[N:26])[C:19]([C:17]#[N:18])=[CH:20]2
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Reactant: N#Cc1ccncc1C#N
Solvent: Clc1ccccc1
Product: N#Cc1cc2c(O)c(-c3ccccc3)c(-c3ccccc3)n2cc1C#N
Reaction time: 2 h

Procedure:
Diphenylcyclopropenone (0.319 g, 1.55 mmol) and 3,4-dicyanopyridine (0.200 g, 1.55 mmol) were mixed in a dry, argon filled reaction flask. Chlorobenzene (2.5 mL) (oxygen free) was added, and the reaction was heated to 130C. After 2 h the heating was stopped and the reaction was allowed to reach room temperature. Petroleum ether 40-60C (2.5 mL) was added in order to obtain a complete precipitate of the product. The solvent was filtered off and the precipitate was washed with petroleum ether. The crude product was stirred with chloroform (30. mL) for lb. The dark chloroform solution was filtered off leaving the title product as a yellow precipitate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:26]([F:27])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:16]2[N:14]3[N:15]=[C:10]([NH:9][CH2:8][CH:6]4[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]4)[CH:11]=[CH:12][C:13]3=[N:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
A solution of compound tert-butyl 2-oxo-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidine-1-carboxylate (114 mg, 0.23 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 30 min and condensed. The residue was purified by prep-HPLC to give 4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidin-2-one (6 mg, 6.6%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH:27][NH2:28]>>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:27]1[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[N:28]1
Reactant: O=C(C=Cc1ccccc1O)c1ccccc1
Reactant: NNc1nc2ccccc2s1
Product: Oc1ccccc1C1=NN(c2nc3ccccc3s2)C(c2ccccc2)C1

Procedure:
Example 4 is prepared using 2-hydroxychalcone and benzothiazol-2-yl-hydrazine following the procedure described for Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]([Cl:8])[CH2:6][CH2:5][CH2:4][CH:3]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[K+].C(OCC)C>CN(C)C=O>[Cl:8][C:7]1[CH:2]([N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC1=CCCCC1Cl
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1C1CCCC=C1Cl
Yield: 73.5 %

Procedure:
A solution of 11.0 g (72.8 mmol) 1,6-dichlorocyclohexene, 20.0 g (108 mmol) potassium phthalimide and 1.0 g (6.0 mmol) potassium iodide in 50 ml dry dimethylformamide was stirred 24 hours at 110° C. under an atmosphere of nitrogen. The reaction mixture was allowed to cool then poured into 30 ml diethyl ether. The dark mixture was filtered, then the ether and DMF removed in vacuo. The dark crystalline residue was dissolved in ethyl acetate then chromatographed on 500 g flash silica eluting with 10% to 20% ethyl acetate/hexane. Concentration of appropriate fractions followed by recrystallization from ethyl acetate/hexane gave 14.0 g (73.5%) of the desired phthalimide, mp 99°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.O.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)nc(Cl)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of 2,6-dichloro-4-nitropyridine (14.82 g, 76.79 mmol) in 350 mL ethanol were sequentially added iron powder (19.91 g, 356.58 mmol), water (65.8 mL, 3.6 mol) and concentrated hydrochloric acid (14.1 mL, 464.1 mmol). After the reaction was performed by stirring for 16 h at 95° C., the reaction solution was cooled to room temperature, adjusted to neutral pH, and subjected to suction filtration. After the filtrate was concentrated, it was extracted with ethyl acetate. The organic phase was combined, dried with anhydrous MgSO4, and subjected to rotary evaporation to afford 11.9 g titled product with a yield of 95.1%.
Reaction SMILES: [Cl:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)C#N.[CH:16]([OH:18])=[O:17].Cl>O>[Cl:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)[C:16]([OH:18])=[O:17]
Reactant: CCCCc1ccc(CC(Cl)C#N)cc1
Reactant: O=CO
Agent: Cl
Solvent: O
Product: CCCCc1ccc(CC(Cl)C(=O)O)cc1
Yield: 77 %

Procedure:
The α-chloro-β-p-butylphenylpropionitrile 2 (166 g, 0.750 moles) was stirred over 240 mL formic acid and 160 mL concentrated HCl at reflux for 16 h. The reaction mixture was cooled, diluted with 300 mL water and washed with ethyl acetate. The ethyl acetate solution was washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The bulk oil solidified on standing. The solid was recrystallized twice from hexane, yielding 139.0 g (0.58 moles, 77% yield) of a white solid, mp. 52.7°-53.6° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:30]=[N:31][CH:32]=C[CH:34]=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[N:40]1C=C(B(O)O)C=NC=1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[N:40][CH:32]=[N:31][CH:30]=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cccnc3)cnc2s1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cncnc3)cnc2s1
Yield: 7 %

Procedure:
Preparation analogous to the synthesis of 25h by using pyrimidine-5-boronic acid (1.5 eq). Purified by HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(pyrimidin-5-yl)thieno[2,3-b]pyrazine-6-carboxamide 25j (2 mg, 7%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.28 (s, 3H), 7.33 (d, J=8.6 Hz, 1H), 7.58-7.67 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.9 (d, J=1.9 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.63 (br s, 1H), 9.37 (s, 1H), 9.51 (s, 1H), 9.61 (s, 2H), 10.38 (br s, 1H). (m/z)=534 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:19](=O)[CH2:18][O:17][CH:16]([CH:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]2=3)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:21]=[C:22]2[C:23]3[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=3[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=3)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC(C=C2c3ccccc3CCc3ccccc32)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (0.05 g) in anhydrous tetrahydrofuran (7 ml) was added a solution of 5-(4-benzyl-5-oxomorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.55 g) in anhydrous tetrahydrofuran (15 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for one hour and refluxed with stirring for 7 hours. The reaction mixture was cooled, admixed with water and extracted with ether. The ether extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(4-benzylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 209° - 210° C (decomp.) (oxalate).
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C.CCOC(C)=O>[N+:18]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]#[N:15])([O-:20])=[O:19]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of sodium thiophenolate (16.29 g, 123.3 mmol) in 150 mL of DMF was heated at 100° C. with 4-chloro-3-nitrobenzonitrile (15.0 g, 82.2 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane giving a yellow solid (4.0 g, 19%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH3:13])[C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:11])(=[O:12])[N:4]([CH3:13])[C:3]=1[C:14](=[O:16])[NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.25 g. of 4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide is heated under reflux for 17 hours with 0.14 g. of 2-aminothiazole in 28 ml. of absolute xylene, while passing a stream of nitrogen through the said mixture. The mixture is cooled to room temperature and crystallization of the product is initiated by scratching. The product is kept overnight in the cold. The precipitate crystals are removed by filtration under suction and recrystallized from ethanol, whereby 4-hydroxy-2-methyl-3-(2-thiazolylcarbamoyl)-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide having a melting point of 226°-227° (with decomposition) is obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[O:27][N:26]=[C:25]([NH2:28])[N:24]=1)([CH3:22])[CH3:21]>>[NH2:28][C:25]1[N:24]=[C:23]([C:20]([NH:19][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:22])[CH3:21])[O:27][N:26]=1
Reactant: CC(C)(N)c1nc(N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1nc(N)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-3-ylamine hydrochloride (1:1) (Example 309 b) as starting materials, LC-MS (UV peak area/ESI) 100%, 358.1872 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:33])([F:32])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[N:22][C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[N:20]2)=[CH:15][CH:14]=1>>[F:3][CH:4]([CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][C:24]([C:21]2[N:22]=[CH:23][N:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][C:11]([F:10])([F:33])[F:32])=[CH:14][CH:15]=3)[N:20]=2)=[CH:25][CH:26]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCOC(=O)CF
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(F)C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil immersion, 0.48 g, 12 mmol) was added to a dry, oven-dried round bottomed flask and placed under nitrogen. Diethyl ether (9 mL) was added, followed by absolute ethanol (0.05 mL), and the reaction was cooled in an ice bath. Ethyl 2-fluoroacetate (0.87 mL, 9.0 mmol) was added dropwise. The reaction was stirred for 15 minutes in ice bath (gas evolution ceased). 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (2.2 g, 6.5 mmol) was added in solid portions. The solution slowly turned color to a golden yellow. The ice bath was removed after 1 hour and warmed to room temperature, stirring for an additional 2 hours until the reaction was quenched with saturated aqueous ammonium chloride, diluted with diethyl ether, and stirred at room temperature for 3 days. The biphasic solution was diluted with brine and extracted with ethyl acetate (2×). The organic layers were dried organic over anhydrous sodium sulfate, filtered, and concentrated to give an orange liquid. The crude material was purified by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent to afford the intermediate ethyl 2-fluoro-3-hydroxy-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate as a crude compound (0.11 g).
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[O:22])[CH2:17]2)=[CH:13][CH:12]=1>>[N:3]1[N:2]([CH2:6][C:7]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1
Reactant: O=C(O)Cn1nccn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 227, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 7.72 (s, 1H), 7.42 (d, 2H), 7.29-7.26 (m, 2H), 7.12 (d, 2H), 7.00 (t, 2H), 6.94-6.89 (m, 4H), 5.28 (d, 2H), 4.85 (d, 1H), 3.51 (t, 1H), 3.15 (t, 1H), 2.96-2.85 (m, 2H), 2.68-2.62 (m, 2H), 1.70-1.61 (m, 1H). MS (EI) for C28H25ClFN5O3 found 534.2 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:6]2[S:5][C:4](=[O:7])[NH:3][C:2]2=[NH:1])[NH:10]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(=O)N1
Solvent: CO
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3.5 parts of 4-imino-2-thiazolidinone, 4.4 parts of 1,3-diiminoisoindoline and 100 parts of methanol was stirred under an atmosphere of nitrogen at room temperature for 3 hours and then at reflux temperature for 2 hours. The reaction mixture was cooled to 25° C. and the solid therein was collected by filtration, washed with fresh methanol and dried in vacuo at 50° C. to obtain 5.4 parts of 1-imino-3-(2-oxo-4-imino-5-thiazolidinylidene)isoindoline as a yellow powder melting at 346°-348° C. (dec).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][C@@H:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@@H:23]4[CH3:22])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 92.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.139 g, 0.69 mmol) according to the example 1, which was given (S)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate as a white solid (0.298 g, 91.2% yield).