Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:13])(=[O:12])([O:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])[NH2:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([C:39](O)=[O:40])[N:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([C:39]([NH:2][S:1](=[O:13])(=[O:12])[O:3][C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])=[O:40])[N:32]=1
Reactant: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Reactant: COc1cc(OC)nc(C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(OC)nc(C(=O)NS(=O)(=O)Oc2c(Cl)cccc2Cl)n1
Reaction time: 3 h

Procedure:
2.4 g of 2,6-dichlorophenyl sulfamate are added in portions at 0° C. to 2° C. to a mixture of 2.3 g of dicyclohexylcarbodiimide, 120 mg of 4-dimethylaminopyridine and 2.2 g of 4,6-dimethoxypyrimidine-2-carboxylic acid in 80 ml of absolute dichloromethane, and stirring is continued for 0.5 hour at 0° C. and 3 hours at room temperature. The mixture is filtered off with suction, the organic phase is washed with 100 ml of 1 N hydrochloric acid and then with water and dried over sodium sulfate. The solvent is distilled off, and the residue is recrystallized from diisopropyl ether. This gives 3.2 g of 2,6-dichlorophenyl N-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]sulfamate of melting point 136°-139° C.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1>CCOCC.[Cu](I)I>[CH2:2]([C:12]1[CH2:13][CH2:14][CH2:15][C:10](=[O:16])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CCCC1
Reactant: BrCc1ccccc1
Agent: I[Cu]I
Agent: [Mg]
Solvent: CCOCC
Product: O=C1C=C(Cc2ccccc2)CCC1
Temperature: -20 °C
Reaction time: 24 h
Yield: 57.6 %

Procedure:
A 500-ml four-necked flask equipped with a thermometer and a condenser was charged with 2.4 g of a piece of magnesium and 120 ml of absolute ether, to which a part of 17 g of benzyl bromide was added with heating. After a reaction started, the remaining amount of benzyl bromide was added dropwise to such a degree that reflux continued. After completion of the drop addition, the resultant mixture was stirred further for 1 hour at room temperature to obtain a liquid reaction mixture. A 500-ml four-necked flask equipped with a thermometer was charged with a suspension of 1 g of copper iodide in 60 ml of absolute ether, to which the liquid reaction mixture was added dropwise at -5° C. After stirring the resultant mixture for 1 hour at the same temperature, it was cooled to -20° C. A solution of 8.6 g of 2-cyclohexen-1-one in 10 ml of absolute ether was added dropwise to the mixture, and the temperature of the resulting liquid reaction mixture was then raised to room temperature while stirring for 24 hours. The liquid reaction mixture was washed with water, dried, filtered and concentrated, and 21 g of the resulting crude product were purified by column chromatography, thereby obtaining 9.6 g (yield: 57%) of 3-benzylcyclohexenone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH:18]([N:21]=[C:22]=[S:23])([CH3:20])[CH3:19]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[S:7]([NH:10][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[S:23])(=[O:8])=[O:9]
Reactant: Cc1csc(N)c1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc(N)c1S(=O)(=O)NC(=S)NC(C)C
Temperature: 52.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of 2-amino-4-methyl-thiophene-3-sulfonamide (0.30 g), potassium carbonate (0.32 g), and isopropyl isothiocyanate (272 μl) in dry acetone (5 ml) under nitrogen was heated at 50-55° C. overnight. Then the solvent was evaporated and the residue was dissolved in water (15 ml); pH was adjusted to 2 by addition of 4 M hydrochloric acid, and the mixture was stirred for 30 min. The precipitated crystals were filtered off, rinsed with a small amount of water and dried to give 0.24 g (yield 54%) of the title compound; m.p. 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
10.0 g (47.5 mmol) 2,6-dichloropyridine-4-carboxylic acid chloride, 7.08 g (47.5 mmol) 4-methyl-3H-benzoxazol-2-one and 32.0 g (240 mmol) aluminium trichloride were heated to 120° C. for 1 h with stirring. The mixture was mixed with ice water and extracted several times with EtOAc. The solid precipitated from EtOAc was suction filtered and washed with EtOAc. The organic phase remaining was separated off, dried on sodium sulphate, filtered and evaporated down. The residue was combined with a little EtOAc, the precipitated solid was suction filtered and washed with a little EtOAc. For further purification the mixture was recrystallised from EtOAc.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C(N(CC)CC)C.[C:18](Cl)(=O)[CH2:19][CH2:20][CH3:21]>ClCCl>[CH2:18]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:19][CH2:20][CH3:21]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione, 6.15 g, 42.7 mmol) and triethyl amine (8.63 g, 85.4 mmol) were dissolved in dichloromethane (60 mL). Butyric acid chloride (4.99 g, 46.9 mmol) was added to the solution thus obtained dropwise while cooling with ice, followed by stirring at room temperature for about 12 hours. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with dilute hydrochloric acid and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=8/2) to obtain 5-butyl-2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH:42]([N:45]=[C:46]=[O:47])([CH3:44])[CH3:43]>>[CH3:43][CH:42]([NH:45][C:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:47])[CH3:44]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methyl-butanamide (Example 2, Step B) and isopropyl isocyanate by the procedure described in Example 2, Step C. 1H NMR (400 MHz, CDCl3): 1.06 (d, 3H) 1.07 (d, 3H), 1.32 (s, 3H), 1.39 (s, 9H), 1.88 (m, 1H), 2.48 (dd, 1H), 2.50 (m, 1H), 2.62 (m, 2H), 3.80 (m, 1H), 4.52 (m, 1H), 4.98 (d, 1H), 5.10 (d, 1H), 5.28 (br s, 1H), 6.08 (br s, 1H), 6.68 (br s, 1H), 7.22 (m, 11H), 7.70 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=N1.N1CCCC1>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([N:35]5[CH2:36][CH2:41][CH2:40][CH2:39]5)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)N5CCCC5)CC4)nc23)c1

Procedure:
Prepared from compound 46 of Example 1 by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23]>C1COCC1>[CH:1]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])=[O:3]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)c1ccc(NC=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Acetic anhydride (268 mL) was added dropwise to formic acid (401 mL) at room temperature, and the reaction solution was stirred at room temperature for 40 minutes. A solution of methyl 4-amino-3-methoxybenzoate (134 g) in THF (600 mL) was added dropwise to the reaction solution at room temperature, and the reaction solution was stirred for one hour. 3.8 L of ice water was added to the reaction solution, and the precipitated solid was filtered and further washed with water (2 L). The resulting solid was dried at 50° C. overnight to obtain 111 g of the title compound. The property values corresponded to the reported values (CAS #700834-18-0).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[CH:18][N:17]=[CH:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CCOC(C)=O>[ClH:29].[ClH:29].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=3)=[CH:18][N:17]=[CH:16]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cncc2Cc2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cc2cncn2CC2CCNCC2)cc1

Procedure:
Into a solution of the product from step C (0.843 g, 2.21 mmol) in EtOAc (200 mL) at 0° C. was bubbled HCl gas. After 10 minutes the solvent was evaporated in vacuo to afford the title compound as a foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[CH2:58][OH:59]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=2[CH2:58][OH:59])=[CH:11][C:10]1=[O:17]
Reactant: OCc1ccc(F)cc1CO
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2CO)cc(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(2,6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (step 1) (3.0 g, 12.65 mmol) was dissolved in N,N-dimethylformamide and cooled to 0° C. Triphenylphosphine (3.98 g, 15.18 mmol) and diethyl azodicarboxylate (2.39 ml, 15.18 mmol) were added and stirred for 10 minutes. 1,2-Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was added and stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred overnight. LC-MS showed only 1 product, not a mixture of regioisomers, as expected. The reaction was added to water and extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. A Biotage silica column was done using 60% ethyl acetate/hexanes as an eluent. Desired product, with a substantial impurity was obtained. Another Biotage silica column was ran using 30% ethyl acetate/hexanes to obtain pure product. The resulting oil was triturated with diethyl ether to obtain a white solid (720 mg, 15%). 1H NMR (300 MHz, CDCl3) δ 7.51-7.39 (m, 2H), 7.26 (dd, J=9.62, 2.51 Hz, 1H), 7.13-7.01 (m, 3H), 6.03 (d, J=2.42 Hz, 1H), 5.96 (d, J=2.41 Hz, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, 1H), 2.02 (s, 3H); LC/MS, tr=2.37 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 376 (M+H). ES-HR/MS m/z 376.1181 (M+H calcd for C20H16F3NO3 requires 376.1155). Identity of the positional isomer was determined from hmbc, 2-D NMR experiments using H to C 2- and 3-bond coupling.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.[I:22]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([I:22])[S:8][C:6]=2[N:7]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 dissolved in THF at −78° C. was added 1.6M solution of n-butyllithium in hexanes). The reaction mixture was stirred at −78° C. for 30 minutes. A solution of iodine in THF was added and reaction mixture was allowed to slowly warm up to room temperature and stirred for 45 minutes. The reaction mixture was quenched with saturated aq. Na2S2O3, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CC(O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:10][NH2:11])[CH:7]=1
Reactant: NN
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: O
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 4,6-dichloro-pyrimidine (18.68 g, 125 mmol), hydrazine monohydrate (18.28 mL, 376 mmol), and 2-propanol (300 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, triturated with water, and filtered. The solid was washed with water, air-dried to give (6-chloro-pyrimidin-4-yl)-hydrazine (16.97 g, Yield 94%): 1H NMR 400 MHz (d6-DMSO) δ 8.83 (s, 1H), 8.17 (s, 1H), 6.76 (s, 1H), 4.50 (s, 2H); MS m/z 145.02 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[O:22]1[CH2:4][CH:3]1[CH2:2][CH2:1][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCOc1ccc(C#N)cc1
Solvent: ClCCl
Product: N#Cc1ccc(OCCC2CO2)cc1
Reaction time: 4 h
Yield: 97.4 %

Procedure:
4-(3-Butenyloxy)benzonitrile (37 g, 0.21 mol; from step (c) above) was mixed with mCPBA (61.6 g, 0.25 mol) and DCM (700 mL) and stirred at r.t for 4 h. The reaction mixture was filtered and 2 mL of DMSO added to destroy the excess mCPBA. The mixture was washed with NaHCO3, then separated, dried and evaporated to give 38.7 g (97%) of the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][S:11][C:10]=2[CH:13]=1
Reactant: Oc1ccc2c(-c3ccc(F)cc3)csc2c1
Reactant: BrCCCBr
Product: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1

Procedure:
In analogy to example 27.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol and 1,3-dibromopropane were converted to yield 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene, MS: 364 (M, 1Br).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5].[CH:14]([NH2:17])([CH3:16])[CH3:15].Cl.CCOCC>CO>[ClH:1].[C:8]1([CH2:7][S:4]([CH2:3][CH2:2][NH:17][CH:14]([CH3:16])[CH3:15])(=[O:6])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(CCCl)Cc1ccccc1
Reactant: CC(C)N
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)NCCS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
A mixture of 51.49 g (0.236 mole) of benzyl 2-chloroethyl sulfone and 600 ml of isopropylamine was stirred at room temperature for 72 hr. The solvent was removed in vacuo, and the residue was partitioned between ether and dilute sodium hydroxide. The ether solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in methanol, and excess ethereal hydrogen chloride was added. Ether was added, and a white solid precipitated to give 43.11 g (65.8%) of a white crystalline solid, m.p. 180.5°-181.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:5][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of 1-methoxy-2-(trifluoromethyl)benzene (10.0 g, 56.8 mmol) in dry chloroform (76 mL) was cooled to 0° C. and treated with chlorosulfonic acid (7.55 mL, 113.5 mmol) drop-wise under argon. After the addition was completed, the reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction was quenched by pouring the mixture slowly onto ice. The separated, aqueous phase was extracted with chloroform (3×). The combined organic phase was washed sequentially with a saturated, aqueous sodium chloride solution (2×) and water. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (8.77 g. 31.9 mmol, 56%) as a gray solid;
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2c(c1)OCO2
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5c(c4)OCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-benzodioxole-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[C:3]([O:27][CH3:28])=[C:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][CH2:13][CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:27][CH3:28])[C:2]([F:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl 4-[2-(5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.0245 g, 0.0623 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0100 g, 0.0685 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(2{-2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0231 g, 71%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([N:24]4[CH2:29][CH2:28][CH:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26][CH2:25]4)[C:20]3=[O:41])=[C:13]([Cl:42])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Cl:17][C:15]1[CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[CH:12]=[C:13]([Cl:42])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([N:24]2[CH2:25][CH2:26][CH:27]([O:30][Si:31]([CH:32]([CH3:33])[CH3:34])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:28][CH2:29]2)[C:20]1=[O:41]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (0.36 g) in THF (5 mL) and methanol (2 mL) with 2N LiOH (5 mL) and stir at room temperature for 3 hours. Partition the mixture between ethyl acetate (25 mL) and 1 N HCl (10 mL). Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 0.34 g (97%) of the title compound. MS (m/z): 619 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3cccnc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(3-pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.98 (t, 2 H), 5.25 (s, 2 H), 6.69 (s, 1 H), 7.21 (m, 7 H), 7.45 (q, 1 H), 7.77 (d, 2 H), 7.91 (d, 1 H), 8.57 (bs, 1 H), 8.70 (bs, 1 H).