Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]4[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=4)=[O:29])[CH2:35]3)[CH2:36][CH2:37]2)=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
A solution of 2-(5-(bromomethyl)-2-fluorophenyl)ethanol [Aromatic Intermediate 2] (5.17 g) in ethanol (20 mL) was added dropwise to a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 1, step b] (9.4 g) and potassium carbonate (6.75 g) in ethanol (75 mL) and the resulting mixture stirred overnight. The mixture was filtered, the filter cake was washed with ethanol (50 mL), and the filtrate and washings combined and evaporated. The residue was partitioned between water (100 mL) and ethyl acetate (250 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate:triethylamine as solvent to give the subtitled compound as a clear oil. Yield 7.9 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]1[C:30]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][CH2:28][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26]1.[CH3:44][C:45]1[S:46][CH:47]=[C:48]([C:50](O)=[O:51])[N:49]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:44][C:45]1[S:46][CH:47]=[C:48]([C:50]([N:34]2[CH2:35][CH2:36][C:30]3([CH2:29][CH2:28][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26][CH2:25]3)[O:31][CH2:32][CH2:33]2)=[O:51])[N:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCCO2)CC1
Reactant: Cc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.322 g) was added in one portion to a solution at 0° C. of tert-butyl 7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step e) (0.176 g) and 2-methylthiazole-4-carboxylic acid (0.093 g) and triethylamine (0.36 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 210 mg.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:22]([CH2:24][NH2:25])[OH:23].O>N1C=CC=CC=1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:23][CH2:22][CH2:24][NH2:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and ethanolamine hydrochloride (1.00 g, 10.3 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (4 mL), and the solution was stirred at room temperature for 3 days. Water (200 mL) was poured into the reaction solution, and the precipitates were suction-filtered. The solid matters were suspended in diethyl ether, and 3 (N) hydrochloric acid (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by stirring at room temperature for 15 minutes. The insoluble matters were suction-filtered. The insoluble matters were dissolved in a mixed solution of ethyl acetate (Wako Pure Chemical Industries, Ltd.) and a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and the mixture was shaken, followed by the separation of the organic layer. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then suction-filtered and concentrated under reduced pressure, to thereby obtain the title compound (0.31 g, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][S:13][CH2:14][S:15]([CH3:17])=[O:16]>C1COCC1>[Cl:1][C:2]1[C:3]([CH:4]=[C:14]([S:13][CH3:12])[S:15]([CH3:17])=[O:16])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cccc(C=O)c1Cl
Reactant: CSCS(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C=C(SC)S(C)=O)c1Cl
Yield: 47.8 %

Procedure:
To a solution of 2-chloro-3-methoxybenzaldehyde 7a (4.65 g, 27.3 mmol) and methyl (methylthio)methyl sulfoxide (4.3 mL, 43.9 mmol) in THF (25 mL) was added a 40% methanolic solution of Triton B (6.2 mL, 13.6 mmol) and the resulting solution was refluxed for 16 hours. After THF was removed, the residue was taken up in ethyl acetate, washed with 1 N HCl, H2O, and brine, then was dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with dichloromethane afforded 2-chloro-1-methoxy-3-[2-(methylsulfanyl)-2-(methylsulfinyl)vinyl]benzene 7b (3.61 g, 48%) as a yellow oil. GCMS (EI) m/z 225 (M+-Cl-16), 210 (M+-Cl-OMe).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[CH3:42][S:43]([O:1][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1)(=[O:45])=[O:44]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(COS(C)(=O)=O)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.122 g, 0.000278 mol) in methylene chloride (2 mL, 0.04 mol) was added triethylamine (0.0775 mL, 0.000556 mol) followed by methanesulfonyl chloride (0.0478 g, 0.000417 mol) at 0° C. The reaction was stirred at rt overnight, quenched with water, extracted with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate, then evaporated to dryness. The crude mixture was used directly in next step (138 mg, 96.02%). LCMS calculated for C23H33N6O4SSi(M+H)+: 517.2; Found: 517.4.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:12]([C:13]3[CH2:14][CH2:15][O:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3]1>CO.[Pd]>[NH:2]1[CH2:3][CH:4]([O:6][C:7]2[C:12]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5]1
Reactant: C1=C(c2cccnc2OC2CNC2)CCOC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1cnc(OC2CNC2)c(C2CCOCC2)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A mixture of 2-(azetidin-3-yloxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridine hydrochloride (see PREPARATION P26.1; 3.5 g, 15 mmol) and wet Pd—C (50%, 1.0 g) in MeOH (100 ml) was stirred under H2 (40 psi) at 30° C. for 3 hours then the reaction mixture was filtered through CELITE® and the filtrate was concentrated in vacuo to give the title compound (3.2 g, 14.6 mmol, yield 91%).
Reaction SMILES: [BH4-].[Na+].[C:3]12[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=O)[O:7][C:5](=[O:6])[C:4]1=[CH:16][CH:17]=[CH:18][CH:19]=2.Cl>CN(C=O)C.O>[CH:19]1[C:3]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:5](=[O:6])[C:4]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
9.0 g (0.24 mol) of sodium borohydride were added in portions at 5° C. in the course of 10 min to a suspension of 50.0 g (0.22 mol) of diphenic anhydride in 220 ml of DMF. After stirring at RT for 1 h, the reaction mixture was poured onto 220 ml of 6 M hydrochloric acid, diluted with 750 ml of water and stirred for 2 h. The deposited precipitate was filtered off with suction and 35.0 g of 7H-dibenzo[c,e]oxepin-5-one were obtained; m.p. 131° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([F:16])[CH2:15][C@@:9]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:22])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@@:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([F:16])[CH2:15][C@@:9]1([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:10](=[O:22])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (1R*,5S*,6S*)-8-benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 36; 795 mg, 66 mmol), 10% palladium on charcoal (250 mg), ethyl acetate (5 ml) and ethanol(10 mi) was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500 ml), filtered through a pad of Celite™. The filtrate was concentrated to give the title compound.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:30]([CH2:33][CH3:34])CC)C>ClCCl>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13][NH:30][CH2:33][CH2:34][S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(CNCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 118.8 %

Procedure:
Dissolve 12.7 g (32 mmol) the compound 10 and 10.2 g (32 mmol) the compound 9 into 60 mL dichloromethane. Then add 6.7 mL (48 mmol) triethylamine followed by a heat flow process for two days. After cooling, wash with 60 mL Sodium hydrogen carbonate aqueous solution, and wash again with 60 mL water, take the organic layer. The organic phase is dried by Na2SO4, condensed and then purified by liquid chromatography (SiO2, ethyl acetate: hexane=1:1) to get light yellow oil product 11 (12.9 g, 59.9%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[N:10]=[C:9]([C:11]2[CH:25]=[CH:24][C:14]3[N:15]([CH3:23])[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:8][S:7][C:6]1=[O:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.C1COCC1>C(N(CC)CC)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[N:10]=[C:9]([C:11]3[CH:25]=[CH:24][C:14]4[N:15]([CH3:23])[C:16]([C:18]5[O:19][CH:20]=[CH:21][CH:22]=5)=[N:17][C:13]=4[CH:12]=3)[CH2:8][S:7][C:6]2=[O:26])=[O:36])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1c(-c2ccco2)nc2cc(C3=NN(CCCN)C(=O)SC3)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccco2)nc2cc(C3=NN(CCCNC(=O)Nc4ccc(Cl)cc4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
120 mg (0.30 mM) of 3-(3-aminopropyl)-5-[2-(2-furyl)-1-methyl-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 50.1 mg (0.33 mM) of 1-chloro-4-isocyanatobenzene are added to 2 ml of THF and 164.33 μl (1.33 mM) of triethylamine. The mixture is stirred at room temperature for 20 hours. The solid is filtered off and washed with water and then with isopropanol to give, after drying, 106 mg of N-(4-chlorophenyl)-N′-{3-[5-[2-(2-furyl)-1-methyl-1H-benzimidazol-5-yl]-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]propyl}urea.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:17]([O:5][C:4]1[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7](=[O:8])[CH:6]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Dimedone (5,5-dimethylcyclohexane-1,3-dione, 99%, 14.2 g), pyridine (9 ml) and methylene chloride (100 ml) were mixed in a flask and butyryl chloride (11.4 g) was added dropwise. The mixture was stirred for 26 hours at room temperature and filtered. The filtrate was washed with HCl (6 N, 100 ml), water (100 ml), saturated Na2CO3 (50 ml), water (50 ml), dried (MgSO4). The solvent was removed under reduced pressure to yield 3-butyroxy-5,5-dimethylcyclohex-2-en-1-one as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]([CH2:32][S:33][C:34]4[S:35][CH:36]=[CH:37][N:38]=4)[O:21][C:20]3=[O:39])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-:40].[Li+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:40])[CH2:32][S:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[C:20]([OH:21])=[O:39])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3C(=O)OC(CSc4nccs4)C3OCc3ccccc3)cc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)O)C(OCc3ccccc3)C(O)CSc3nccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-4-phenylmethoxy-5-[[(2-thiazolyl)thio]methyl]-tetrahydrofuran 63f, 154 mg, 0.258 mmol) is dissolved in THF/water (2 mL/2 mL) and lithium hydroxide (108 mg, 2.58 mmol) is added and the reaction is stirred for two hours at room temperature. The reaction is concentrated to remove the solvent, diluted with water and extracted (2 times) with ether. The aqueous layer is neutralized with 1N HCl to pH6 and extracted with ethyl acetate (3 times). The combined organic layer is washed with brine, dried over magnesium sulfate, and the solvent removed in vacuo. The crude material is adsorbed onto silica gel and purified over a short silica column eluting with hexane/ethyl acetate (1/1) followed with ethyl acetate and ethyl acetate/methanol (8/2). Product fractions are combined and dried to give the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]=[O:12]>CO>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]([OH:12])[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3]
Reactant: C=CC(=O)OCC
Reactant: COC(C=O)OC
Solvent: CO
Product: C=C(C(=O)OCC)C(O)C(OC)OC

Procedure:
118 mmoles ethyl acrylate and 10 g (86.5 mmoles) of 90% by weight dimethoxyethanal in methanol were reacted using the method of example 1 to form 4,4-dimethoxy-2-ethoxycarbonyl-3-hydroxy-1-butene as a liquid which distilled at 108° C. under 0.3 mbar.
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])I.CN(C=O)C>C1(C)C=CC=CC=1.[Cu]>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:26]([F:29])([F:28])[C:25]([F:30])([F:31])[C:24]([F:32])([F:33])[C:23]([F:35])([F:34])[F:22])[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4]1
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (2.47 g), copper powder (1.14 g), nonafluoro-1-iodobutane (4.15 g) and DMF (16 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 130-135° C. After cooling to room temperature, the reaction mixture was diluted with toluene (50 ml) and an insoluble matter was filtered with Celite and washed with toluene. The filtrate was concentrated under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-nonafluorobutyl-3-trifluoromethyl-1H-pyrazole (1.50 g).
Reaction SMILES: O1C=CC([C:6]2([C:19](=[O:21])[CH3:20])[N:13]3[C:9]([S:10][C:11]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:12]=43)=[N:8][CH2:7]2)=C1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O>>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=[CH:20][C:19]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:12]=32)=[N:8][CH:7]=1)=[O:21]
Reactant: CC(=O)C1(c2ccoc2)CN=C2SC3=C(CCCCC3)N21
Reactant: O=Cc1ccco1
Product: O=C(C=Cc1ccco1)c1cnc2sc3c(n12)CCCCC3

Procedure:
3-(3-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula P-1), 3.51 g, was condensed with 2-Furaldehyde (1.99 g) by non-critical variations of PREPARATION 15 to give 3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula P-2, X=0), m.p. 161-162°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:10]=2)[O:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0° C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C. and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Mg SO4 and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole as a crude material. LC/MS (M+H)+: 325, 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.80(s, 1H), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H), 0.95(t, 2H), 0.0(s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH-:20].[K+]>O1CCCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(Cl)nc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A solution of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (336.5 mg, 1.06 mmol) in tetrahydrofuran (6 mL) was treated with a 2N aqueous potassium hydroxide solution (6 mL) and was warmed to 80° C., where it stirred overnight. At this time, the reaction was concentrated in vacuo and was then carefully brought to pH ˜7 with a 2N aqueous hydrochloric acid solution. The material was then diluted with water (25 mL) and extracted with a 10% methanol/methylene chloride solution (2×25 mL). The combined organics were dried over magnesium sulfate, filtered and rinsed with methylene chloride, and concentrated in vacuo onto Celite®. Flash chromatography (40 g silica gel column, 1-50% ethyl acetate/hexanes) afforded 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one as an off-white solid (53.7 mg, 16.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.08 (s, 9H) 0.82 (t, J=8.10 Hz, 2H) 3.50 (t, J=8.10 Hz, 2H) 5.42 (s, 2H) 6.53 (d, J=3.20 Hz, 1H) 7.26 (br. s., 1H) 12.98 (br. s., 1H). LC-MS calcd. for C12H19ClN3O2Si [(M+H)+] 300, obsd. 300.0.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20](O)=[O:21])[CH2:3][CH2:2]1.Cl.Cl.[CH3:25][C@H:26]1[C@H:31]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH2:29][NH:28][CH2:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:28]2[CH2:29][CH2:30][C@H:31]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[C@@H:26]([CH3:25])[CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: C[C@@H]1CNCC[C@H]1N1CCCC1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CC[C@H](N2CCCC2)[C@@H](C)C1

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and (trans)-3-methyl-4-pyrrolidin-1-yl-piperidine dihydrochloride (example 195C) in direct analogy to the general procedure used in example 150. MS: 461.3 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 60 °C
Yield: 43.3 %

Procedure:
The suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 1.81 mmol) was treated with N,N-diisopropylethylamine (411 uL, 2.36 mmol) followed by 2-chloro-N,N-dimethylacetamide (192 uL, 1.42 mmol). The mixture was heated at 60° C. for 3 h then cooled to rt. The white solid was filtered then purified by ISCO® using 0-10% 2N NH3 in MeOH/EtOAc. 313 mg (52.1%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.42 (s, 1H), 8.04 (s, 1H), 8.19-8.12 (m, 2H), 7.82-7.70 (m, 5H), 7.62-7.60 (d, 1H), 6.99 (s, 1H), 6.02 (s, 2H), 5.96 (s, 2H), 3.70-3.59 (m, 3H), 3.50 (s, 3H), 3.48-3.40 (m, 2H), 3.36 (s, 3H), 2.79-2.50 (m, 2H), 2.59-2.48 (m, 2H), 2.36-2.24 (m, 2H); LC-MS m/z[M+H]+ 509.2, RT 2.09 min.