Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=4)[N:15]=[CH:14][CH:13]=3)=[CH:10][C:2]1=2.[CH3:25][C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)[CH:27]=1.C(N(CC)CC)C>C1COCC1>[OH:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:23][CH3:24])[N:15]=[CH:14][CH:13]=[C:12]2[O:11][C:9]1[CH:8]=[CH:7][C:3]2[N:4]([C:32]([NH:31][C:28]3[CH:27]=[C:26]([CH3:25])[O:30][N:29]=3)=[O:33])[CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)no1
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Nc3cc(C)on3)c2cc1O
Temperature: 50 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
A resealable tube was charged with 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yloxy)-7-methoxyquinolin-6-ol (0.200 g, 0.617 mmol), 4-nitrophenyl 5-methylisoxazol-3-ylcarbamate (0.243 g, 0.925 mmol), and THF (5.0 mL). Triethylamine (0.258 mL, 1.85 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 50° C. for 15 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow-orange oil. This material was purified via column chromatography on silica gel (RediSep 40 g column, eluting with 5% methanol-dichloromethane) to afford a yellow oil. This material was triturated with dichloromethane and filtered to afford 7-(6-hydroxy-7-methoxyquinolin-4-yloxy)-N-(5-methylisoxazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxamide (0.104 g, 38% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=O.[CH3:14][CH:15]1[NH:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:20]2[CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH:15]2[CH3:14])=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1NCCNC1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1C(=O)NCCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 69.7 %

Procedure:
A solution of 3,4-dichlorocinnamic acid (190 mg, 0.88 mmol), 3-methylpiperazin-2-one (100 mg, 0.88 mmol), 4-methylmorpholine (443 mg, 4.38 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (500 mg, 1.31 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 3 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH 95:5) produced the title compound (192 mg, 70%). White solid, MS (ISP)=313.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:2]12.[Cl-].[Li+]>CN1CCCC1=O>[C:2]1(=[O:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCCCC2OC2CCCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCCCCCCCCCCCC1
Temperature: 200 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
A mixture containing 10.5 g of epoxy-cyclohexadecane, 10 g of N-methylpyrrolidone, and 0.5 g of lithium chloride was stirred at 200° C. for 6 hours. With a 100% conversion, a 98.9% yield of cyclohexadecanone was obtained.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:42][CH:41]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[N:45]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:42][CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 24.9 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.01 g), N-(6-bromo-2-pyridyl)acetamide (1.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.138 g), the title compound (0.720 g) was obtained as colorless powder crystals.
Reaction SMILES: [CH:1](Br)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Mg].Cl/[CH:11]=[CH:12]/[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ni+2].[Br-]>[CH2:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=C/C=C/Cl
Reactant: CCCCCC=CBr
Agent: [Ni+2]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C/C=C/C=C/CCCCC
Temperature: 35 °C

Procedure:
1.3 millimoles of nickel (2+) bis(triphenylphosphine) bromide and 100 millimoles of magnesium 1-heptenyl bromide (mixture of two isomers Z and E in a ratio by weight of 6:4), dissolved in tetrahydrofuran, are added, under nitrogen and while cooling, to a solution of 50 millimoles of (E)-1-chloro-1,3-butadiene in 200 ml of tetrahydrofuran. The mixture is heated at 35° C. for approximately 1 hour and the reaction medium is then hydrolysed with a saturated ammonium chloride solution. The mixture is decanted. The organic phase is washed twice with 25 ml of the saturated aqueous solution each time. The organic phase is dried over anhydrous magnesium sulphate. The solvent is removed by evaporation under reduced pressure (20 mmHg) and at a temperature of 30° C. A mixture of (3E,5Z)-1,3,5-undecatriene (I) and (3E,5E)-1,3,5-undecatriene (II) is obtained. The mixture is distilled under reduced pressure (0.02 mmHg) and at a temperature of 30° C. in order to obtain a pure mixture of two isomers in a ratio by weight of 6:4.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OCCCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.022 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Hexyl acrylate (8.8 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 4 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid hexyl 4,4-dinitropentanoate (4.5 g, yield: 81%).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: COc1cccc(CN)c1
Agent: Cl
Product: COc1cccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (3-methoxybenzyl)amine instead of (pyridin-2-ylmethyl)amine. The crude product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 5H), 1.60-1.80 (m, 5H), 1.87 (s, 3H), 2.21 (s, 3H), 3.72 (s, 3H), 3.86 (s, 1H), 4.48 (d, J=5.64 Hz, 2H), 6.75-6.89 (m, 3H), 7.23 (t, J=7.93 Hz, 1H), 7.56 (d, J=7.52 Hz, 1H), 8.40-8.55 (m, J=38.95 Hz, 1H), 12.56 (s, 1H); MS (ESI) m/z 341.5 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[CH:5][CH:4]=1.[CH2:8]([O:10][P:11]([O:15]CC)[O:12][CH2:13][CH3:14])[CH3:9]>>[O:7]1[C:3]([CH2:2][P:11](=[O:15])([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9])=[CH:4][CH:5]=[N:6]1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccno1
Product: CCOP(=O)(Cc1ccno1)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
5-(Bromomethyl)isoxazole (5.38 g, 33.2 mmol) was stirred at 0° C. as triethylphosphite (5.7 mL, 33.2 mmol) was slowly added. The mixture was stirred at room temperature for 48 h, heated under reflux for 24 h, then concentrated. Purification by distillation at reduced pressure (bp 109-115° C./0.04 mm Hg) provided pure product as a colorless oil (6.75 g, 92.7%).
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(NC1CCN(C(OC(C)(C)C)=O)CC1)=O.Cl.[Br:26][C:27]1[CH:28]=[C:29]([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:34])[NH:30][C:31]=1[CH3:32].[F:42][C:43]([F:57])([F:56])[C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[C:47]([C:53](O)=[O:54])[NH:48]2>>[Br:26][C:27]1[CH:28]=[C:29]([C:33]([NH:35][CH:36]2[CH2:37][CH2:38][N:39]([C:53]([C:47]3[NH:48][C:49]4[C:45]([CH:46]=3)=[C:44]([C:43]([F:57])([F:42])[F:56])[CH:52]=[CH:51][CH:50]=4)=[O:54])[CH2:40][CH2:41]2)=[O:34])[NH:30][C:31]=1[CH3:32]
Reactant: O=C(O)c1cc2c(C(F)(F)F)cccc2[nH]1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(C(=O)c3cc4c(C(F)(F)F)cccc4[nH]3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Intermediate 2 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 4-(trifluoromethyl)-1H-indole-2-carboxylic acid (J. Am. Chem. Soc. 1957, 79, 1745).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:10]([CH2:11][C:12](=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
7-Oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.7 g, 48.6 mmol) was dissolved in methylene chloride (100 mL). Et3N (13.5 mL, 97.3 mmol) and 4-chlorobenzenesulfonyl chloride (12.3 g, 58.4 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous phase was separated and extracted once with methylene chloride (50 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane/EtOAc, 20/1 to 1/1) to give 16.6 g (82%) of 9-(4-chloro-benzenesulfonyl)-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=2.164, method [1], MS(ESI) 437.0 (M+Na); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 4.40 (d, J=4.4 Hz, 2H), 4.18-3.95 (m, 2H), 2.95-2.81 (m, 2H), 2.59 (dd, J=15.9, 6.0 Hz, 2H), 2.38 (d, J=15.9 Hz, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:28])[CH2:22][CH:21]([CH2:23][CH2:24][NH2:25])[CH2:20][C:19]([CH3:27])([CH3:26])[NH:18]1>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7]([NH:25][CH2:24][CH2:23][CH:21]2[CH2:22][C:17]([CH3:28])([CH3:16])[NH:18][C:19]([CH3:27])([CH3:26])[CH2:20]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc(NCC=C)n1
Reactant: CC1(C)CC(CCN)CC(C)(C)N1
Solvent: Cc1ccccc1C
Product: C=CCNc1nc(NCC=C)nc(NCCC2CC(C)(C)NC(C)(C)C2)n1

Procedure:
18.05 g (0.08 mole) of 2,4-bis-allylamino-6-chloro-1,3,5-triazine and 14.74 g (0.08 mole) of 2-(2,2,6,6-tetramethylpiperid-4-yl)-ethylamine in 130 ml of xylene are heated at reflux temperature for 4 hours, while stirring. 3.5 g (0.088 mole) of finely powdered sodium hydroxides are then added to the reaction mixture in 4 portions over a period of 4 hours, and the mixture is kept at reflux temperature overnight. The reaction mixture is then freed from the precipitated sodium chloride by filtration while hot, the xylene is completely removed by vacuum distillation, and the residue is recrystallised from n-pentane. The 2,4-bis-allylamino-6-[2-(2,2,6,6-tetramethylpiperid-4-yl)-ethylamino]-1,3,5-triazine thus obtained has a melting point of 74°-75° (stabiliser No. 14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](OC3C=CC(N)=CC=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1>CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:4]3[CH:3]=[CH:8][C:7]([C:35]([C:32]4[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=4)=[O:36])=[CH:6][C:5]=3[NH2:13])[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Oc3ccc(N)cc3)n2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(-c3ccc(C(=O)c4ccc(Cl)cc4)cc3N)n2)cc(OC)c1OC
Yield: 34 %

Procedure:
Using Method LL with 2-(3,4,5-trimethoxyphenylamino)-6-(4-aminophenyloxy)-pyrazine (50 mg, 0.14 mmol) and 4-chlorophenylcarbonyl chloride (22 μL, 0.17 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (23 mg). Yield: 34%. 1H NMR (250 MHz, DMSO-d6) δ 3.65 (s, 3H, [CH3O]4), 3.85 (s, 6H, [CH3O]3+5), 7.28 (s, 2H, Harom2′+6′), 7.64 (d, 2H, Harom 3+5, J=8.5 Hz), 7.93 (d, 2H, Harom 3″+5″, J=8.6 Hz), 7.93 (m, 2H, Harom 2″+6″), 8.03 (m, 2H, Harom 2+6), 8.14 (s, 1H, HPz 5), 8.53 (s, 1H, HPz 3), 9.56 (s, 1H, NH), 10.50 (s, 1H, NHamide). m/z 491.1 [(M+H)+ calcd for C26H23ClN4O4 490.1].
Reaction SMILES: C1COCC1.[Br-].[F:7][CH2:8][CH2:9][CH2:10]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:36][C:37]1[CH:38]=[C:39]([CH:47]2[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]2)[CH:40]=[C:41]([F:46])[C:42]=1[O:43][CH2:44][CH3:45]>O>[F:36][C:37]1[CH:38]=[C:39]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:10][CH2:9][CH2:8][F:7])[CH2:49][CH2:48]2)[CH:40]=[C:41]([F:46])[C:42]=1[O:43][CH2:44][CH3:45]
Reactant: FCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1c(F)cc(C2CCC(=O)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(F)cc(C2CCC(CCCF)CC2)cc1F
Temperature: -50 °C
Yield: 21 %

Procedure:
THF (100 ml) was added to the above 3-fluoropropyltriphenylphosphine bromide (22.0 g, 54.6 mmol), followed by cooling the mixture down to -50° C. in a nitrogen atmosphere, adding to the mixture, a 70 ml THF solution of potassium-t-butoxide (6.10 g, 54.5 mmol), stirring the mixture for 3 hours, dropwise adding to the reaction solution, a 80 ml THF solution of 4-(3,5-difluorophenetyl)-1-cyclohexanone (10.0 g, 42.0 mmol), stirring the mixture for one hour at the same temperature, and heating it up to room temperature for 4 hours, adding water (200 ml) to the resulting reaction solution, extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying the organic layer over magnesium sulfate, distilling off the solvent under reduced pressure, purifying the residue according to column chromatography treatment using toluene as a developing solvent, hydrogenating the resulting purified substance in the presence of 5% Pd/C catalyst, in ethanol, and thereafter filtering off the catalyst to obtain 4-(3,5-difluorophenetyl)-1-(3-fluoropropyl)cyclohexane (2.51 g, 8.83 mmol). Yield: 21.0%.
Reaction SMILES: Cl[Si](C)(C)C.[BH4-].[Li+].[F:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]#[N:21])[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16]>O1CCCC1.CO>[F:8][C:9]1[CH:10]=[C:11]([CH2:19][CH2:20][NH2:21])[CH:12]=[CH:13][C:14]=1[C:15]([F:17])([F:18])[F:16]
Reactant: N#CCc1ccc(C(F)(F)F)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
Chlorotrimethylsilane (2 mL, 16 mmol) was added dropwise to lithium borohydride (2M in tetrahydrofuran, 4 mL, 8 mmol). A solution of 3-fluoro-4-(trifluoromethyl)phenylacetonitrile (312 mg, 4 mmol) in tetrahydrofuran (2 mL) was then added at 0° C. and the mixture was allowed to stir for 24 hours, whilst warming to room temperature. The mixture was then diluted with methanol (20 mL) and concentrated in vacuo. The residue was taken up in 20% potassium hydroxide solution (20 mL), extracted with dichloromethane (3×20 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Isolute® SCX-2 cartridge, eluting with methanol followed by 1M ammonia in methanol, to give an oily residue. The oil was triturated with diethyl ether to afford the title compound in 59% yield, 485 mg. H NMR (400 MHz, CDCl3) δ: 7.53 (1H, m), 7.08 (2H, m), 3.02 (2H, t) 2.82 (2H, t) ppm; LRMS APCI m/z 208 [M+H]+
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.[Br:12][C:13]1[C:14](N(C(CC)C)CCC(NC)=O)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1>>[Br:12][C:13]1[C:14]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: CCC(C)N(CCC(=O)NC)c1nc(Cl)ncc1Br
Reactant: CNC(=O)CCNCC1CC1
Product: CNC(=O)CCN(CC1CC1)c1nc(Cl)ncc1Br

Procedure:
Using 3-(cyclopropylmethylamino)-N-methyl-propanamide—Intermediate 95 and analogous conditions to Intermediate 88 the title compound was obtained as a white solid (431 mg)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:4]=[N:3]1.O=P(Cl)(Cl)Cl.CN([CH:23]=[O:24])C>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:23]=[O:24])=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:4]=[N:3]1
Reactant: CN(C)C=O
Reactant: Cn1ncc(N2CCCCC2)cc1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc(N2CCCCC2)c(C=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methyl-5-(piperidin-1-yl)pyridazin-3(2H)-one [F. Farina, M. V. Martin and A. Tito, An. Quim., 77, 188-195 (1981)] (1.35 g, 7 mmol) in dry DMF (23.3 ml) was cooled to 5° C., then a solution of POCl3 (1.44 ml, 15.4 mmol) in dry DMF (3.5 ml) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. Then, the temperature was raised to 70° C. and stirring was continued for 75 min. After cooling, the volatile components were removed under reduced pressure and the residue was treated with crushed ice (15 g). The mixture was adjusted to pH 7-8 with aqueous NaOH. Then it was extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. Residual volatile material was removed at 10−2 mbar to leave an oily residue which slowly solidified on storage in a refrigerator.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[N:25]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([S:42]([N:19]2[CH2:20][CH2:21][CH:17](/[CH:16]=[CH:15]/[C:13]3[CH:12]=[CH:11][C:10]([N:22]4[S:26](=[O:27])(=[O:28])[N:25]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:24](=[O:35])[CH2:23]4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:14]=3)[CH2:18]2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCNC3)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCN(S(=O)(=O)c4ccccc4)C3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-((E)-2-pyrrolidin-3-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and benzenesulfonyl chloride analogous to Example 192, step B.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]=1[C:16]([OH:18])=O>>[Cl:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]=1[C:16]([Cl:3])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)ccc2c1OCCO2
Product: O=C(Cl)c1c(Cl)ccc2c1OCCO2
Yield: 93 %

Procedure:
56 ml of thionyl chloride, 28 g of 6-chloro-1,4-benzodioxane-5-carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a condenser and a thermometer. The mixture was heated at the reflux temperature for 30 minutes. The excess of thionyl chloride was removed by distillation under reduced pressure. 28.5 g of 6-chloro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 50° C.; yield: 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]NC(=O)C2C=CC(N3CCCC3)=CC=2)=[CH:9][CH:8]=1)[CH3:2].[C:29]1([S:35](CC2C=CC(CO)=CC=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=S(=O)(Cc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCCC3)cc2)cc1
Product: CCOC(=O)C=Cc1ccc(CS(=O)(=O)c2ccccc2)cc1
Yield: 82 %

Procedure:
The titled compound was prepared as described in the process (5-2) using the compound from the process (10-3).