Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>N1C=CC=CC=1>[C:14]([O:12][CH2:11][CH:9]1[CH2:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]([F:13])[C:6]=2[O:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1Cc2c(F)ccc(F)c2O1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC1Cc2c(F)ccc(F)c2O1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
4,7-Difluoro-2,3-dihydro-2-hydroxymethylbenzofuran (1.2 g) was dissolved in 6 ml pyridine, then 0.73 ml acetic anhydride was added thereto at 0° C. in a nitrogen stream, and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into 10% aqueous hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 750 mg 2-acetoxymethyl-4,7-difluoro-2,3-dihydrobenzofuran as a colorless oil.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[NH:22]N.CS(O)(=O)=O>C(O)C>[N:1]1([CH:7]2[CH2:12][C:11]3[C:17]4[C:16](=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=4)[NH:22][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C1CCC(N2CCCCC2)CC1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Fc1cc(F)c2[nH]c3c(c2c1)CC(N1CCCCC1)CC3

Procedure:
A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for twelve hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. >290° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=4[N:19]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2>C(#N)C.CN(C)C=O>[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][N:22]1[C:17]1[C:18]2[N:19]=[C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][NH:1][C:5]4=[N:6][CH:7]=3)[CH:11]=[CH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=c1[nH]cnc2ccc(-c3cnc4[nH]ccc4c3)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc2c(c1)CCN(c1ncnc3ccc(-c4cnc5[nH]ccc5c4)nc13)C2
Temperature: 60 °C
Yield: 65 %

Procedure:
0.20 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and 139 μl of 1,2,3,4-tetrahydroisoquinoline are suspended in 10 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.65 g of (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate, 255 μl of 1,8-diaza-bicyclo[5.4.0]undec-7-ene are subsequently added, and the mixture is heated at 60° C. under nitrogen until the reaction has proceeded to completion (HPLC check, about 5 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.20 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine (“A6”) as white solid (yield 65%, content 94%); MS-FAB (M+H+)=379.1; Rf (polar method): 1.86 min;
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][CH:35]=[C:26]([CH2:25][N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:13]2=[O:21])[CH:27]=1
Reactant: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)n(Cc3cccc4ccccc34)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
To a solution of 1-Naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.37 mmol) in DMF (3 mL) was added 60% NaH (22 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 10 min and then Methyl 3-(bromomethyl)benzoate (0.1 g, 0.44 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. When the reaction was complete, the mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 100% CH2Cl2 as an elunet to afford 0.14 g of the desired product as a white foam. LCMS (ESMS): m/z 423.84 (M+H+).
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])(=O)C.O.[I:24](O)(=O)=O>>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:7][CH2:6][CH2:5][I:24]
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)OCCCC(c1ccccc1C)c1ccccc1C
Solvent: O
Product: Cc1ccccc1C(CCCI)c1ccccc1C

Procedure:
The crude 2,2-di-(2-tolyl)-tetrahydrofuran 33a (28 g) was dissolved in acetic acid (250 mL). 5% palladium on Carbon black (3 g) was added and the mixture was hydrogenated in a Parr apparatus at 3 ato at 55° C. for 5 hrs. The catalyst was filtered off and the solvent was evaporated in vacuo. The remaining oil was subjected to CC (n-heptane/ethyl acetate—15:1) to give 4,4-di-(2-tolyl)-i-butanol (17 g). A solution of 4,4-di-(2-tolyl)-i-butanol (19 g) in acetic acid (400 mL) was boiled under reflux for 3 hrs. The cooled solution was evaporated in vacuo to give 4,4-di-(2-tolyl)-i-butyl acetate (17 g) as an oil. A solution of 4,4-di-(2-tolyl)-l-butyl acetate (9.2 g) in 57% aqueous iodic acid (150 mL) was boiled under reflux for 3 hrs. The cooled solution was poured into a mixture of ice and water and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which was used without further purification. 1H NMR (CDCl3) δ 1.80-2.10 (m,4H), 2.28 (s,6H), 3.17 (t,2H), 4.26 (t, 1H), 7.12 (s,8H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:43])[C:17]4[C:22]([C:23]=3[C:24]3[CH2:25][CH2:26][N:27]([C:30]([CH:32]5[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]5)=[O:31])[CH2:28][CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[F:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[C:49]([OH:51])[CH:50]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:43])[C:17]4[C:22]([C:23]=3[C:24]3[CH2:25][CH2:26][N:27]([C:30]([CH:32]5[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]5)=[O:31])[CH2:28][CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:47]3[CH:48]=[C:49]([OH:51])[CH:50]=[C:45]([F:44])[CH:46]=3)[C:3]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 63.1 %

Procedure:
The title compound was prepared following the procedure reported for Example 68, from tert-butyl 3-(4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidine-1-carboxylate (Intermediate D28, 0.251 g, 0.360 mmol), and 3-fluoro-5-hydroxyphenylboronic acid (0.112 g, 0.720 mmol) to give tert-butyl 3-(4-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidine-1-carboxylate (0.155 g, 0.227 mmol, 63.2% yield).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of dec-9-en-1-ol (1.22 g, 7.82 mmol) in DMF (18 mL) was added triphenylphosphine (2.30 g, 8.77 mmol). The solution was cooled to 0° C. and NBS (1.52 g, 8.54 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.8 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 10-bromo-dec-1-ene (1.38 g, 81%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.80 (1H, m), 4.94 (2H, m), 3.38 (2H, t, J=6.9 Hz), 2.02 (2H, m), 1.83 (2H, m), 1.20–1.55 (10H, m); 13C NMR (75 MHz, CDCl3) δ 139.17, 114.30, 34.29, 34.02, 33.06, 29.53, 29.25, 29.12, 28.96, 28.40.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:12]#[N:13])[NH:6][C:7](=O)[CH:8]([CH3:10])[CH3:9])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1.CCCCCCC.C1COCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[S:24][C:12]=1[NH2:13])=[O:14])[CH3:2]
Reactant: CCOC(=O)C(C#N)NC(=O)C(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C(C)C)sc1N
Yield: 392.2 %

Procedure:
Stir cyano-isobutyrylamino-acetic acid ethyl ester (139 g, 701 mmol) mechanically stir as a slurry in toluene (1.4 L) at rt under N2. Add lawesson's reagent (170 g, 420 mmol, 0.6 eq.) in portions and heat the thick slurry to 70° C. and stir for 12 hours until complete by TLC (2:1/heptane:THF). Cool the mixture and concentrate to dryness in vacuo on a rotovapor to obtain 353 g of thick yellow oil that was partially purified by silica gel plug (1 Kg silica gel 60, 1.5 vol. warm 2:1/THF:heptane as diluent, 2:1/heptane:THF as eluent). Combine the product containing filtrates and concentrate to dryness in vacuo on a rotovapor to obtain 194 g of crude solid. Dissolve the solid in EtOAc (400 mL) at 50–60° C. with stirring, then allow to cool gradually to rt. Precipitate the product and was cool to 0–5° C. with stirring for 30 minutes, isolate by suction filtration, rinse with cold EtOAc (2×50 mL), then dry in a vacuum oven at 50° C. to afford a first crop of 76.3 g (51%) of the title compound. Obtain a second crop of 17.6 g (12%)=from the filtrate after concentration in vacuo and silica gel chromatography (1 Kg silica gel 60, 2:1/heptane:THF). 1H NMR (300 MHz, DMSO-d6) δ 7.23 (bs, 2H), 4.21 (q, 2H, J=6.95 Hz), 3.02 (dq, 1H, J=6.95 Hz), 1.27 (t, 3H, J=6.95 Hz), 1.22 (d, 6H, J=6.95 Hz). 13C NMR (75 MHz, DMSO-d6) δ 163.72, 160.08, 156.20, 118.08, 58.99, 32.27, 22.35 (2), 14.46. IR (CHCl3) 3483, 3347, 2975,2933, 2868, 1668, 1582, 1530, 1494, 1464, 1409, 1382 cm−1. HRMS (ES) M/z calculated for C9H14N2O2S 215.0854, found 215.0842.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 8-methoxy-9-[4-(piperazin-1-yl)phenyl]thieno[2,3-c]quinolin-4(5H)-one (89 mg, 0.23 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.42 mL, 0.68 mmol) and methanesulfonyl chloride (45 μL, 0.27 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified by preparatory HPLC (C18 silica, acetonitrile/water w/0.05% TFA gradient) to afford the desired product (72 mg, 68%) as a brown solid: ESI MS m/z 470 [C23H23N3O4S2+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.C(OCC)(=O)C.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>O>[CH:25]([O:24][C:22]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq), triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g) was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at a rate sufficiently slow to maintain the reaction mixture temperature at 10°-17° C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred at 20° C. for 18 hours. Then water (100 g) was added, and the resulting mixture was stirred for 15 minutes before the phases were separated. The organic phase was washed with two 100-gram-portions of 20 wt % aqueous NaCl by stirring for 15 min at 150 rpm before separating the aqueous wash. After a final wash with water (100 g), the organic phase was concentrated by distillation on a rotary evaporator at reduced pressure to provide product (2) (91.1 g, 92.0% yield) as light amber oil of 96.8% purity by GC. Distillation of this crude product at 117-120° C., 0.3-1.0 torr gave a 95.7% recovery of product (2) as a colorless oil collected at 112°-119° C.
Reaction SMILES: [CH:1]1[C:6]([C@H:7]2[O:16][C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([OH:18])[C:10]=3[CH2:9][C@H:8]2[OH:19])=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[OH:21][C:3]1[CH:2]=[CH:1][C:6]([C@@H:7]2[C@H:8]([OH:19])[CH2:9][C:10]3[C:15](=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[OH:18])[O:16]2)=[CH:5][C:4]=1[O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Oc1cc(O)c2c(c1)O[C@H](c1ccc(O)c(O)c1)[C@H](O)C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc([C@H]2Oc3cc(O)cc(O)c3C[C@H]2O)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (−)-epicatechin (1.16 g, 4 mmol) and potassium carbonate (1.1 g, 8 mmol) in DMF (10 mL) at −20° C. was added ethyl bromoacetate (490 mL, 4.4 mmol). The reaction was stirred at the same temperature for 2 hr, allowed to warm to RT, and stirred for 2 hr. The reaction was diluted with ethyl acetate, washed with citric acid then brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative reverse phase HPLC using a gradient of 10% to 80% acetonitrile/(0.2% formic acid/water) over 20 min, analyzing at 280 nm. The appropriate fractions were frozen and lyophilized to give as white powders:
Reaction SMILES: [CH2:1]=[O:2].C([Al](CCCCCCCC)[CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])CCCCCCC>CCCCCC>[CH2:1]([OH:2])/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC=C[Al](CCCCCCCC)CCCCCCCC
Reactant: C=O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CO
Yield: 27.2 %

Procedure:
Similarly to the procedure described in Example 1, a 25% slurry of 144 grams (4.80 moles) of paraformaldehyde in n-hexane was treated with 1083 grams (4.59 moles) is di-n-octyl decenyl aluminum (prepared from tri-n-octyl aluminum and acetylene). Distillation of the hydrolysis product was performed under 2 mm Hg. The product fraction was removed at 85°-95° C. There was obtained 210 grams (1.25 moles) of cis-2-undecen-1-ol (27.2% of theoretical yield), having a purity of 91%. Identity of the compound was confirmed by ir and nmr spectral analyses.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=O)[CH:4]=1)#[N:2].[N-:23]=[N+:24]=[N-:25].[Na+].C(#N)C.Cl[Si](Cl)(Cl)Cl>O.O1CCCC1>[C:8]1([C:7]2[C:3]([C:1]#[N:2])=[CH:4][N:5]([C:14]3[CH:15]=[C:16]([C:17]4[NH:25][N:24]=[N:23][N:19]=4)[CH:20]=[CH:21][N:22]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cn(-c2cc(C(N)=O)ccn2)cc1-c1ccccc1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: N#Cc1cn(-c2cc(-c3nnn[nH]3)ccn2)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 2-(3-cyano-4-phenylpyrrole-1-yl)isonicotinamide (0.058 g) and sodium azide (0.039 g) in a mixed solvent of acetonitrile (1.0 mL) and tetrahydrofuran (0.5 mL) was added tetrachlorosilane (0.068 g) at room temperature, and this mixture was stirred at 80° C. overnight. To this reaction mixture was added water, this obtained solid was collected by filtration. After washing with water, this solid was dried at 50° C. under reduced pressure to give the title compound (0.051 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]=[C:8]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]2[CH2:24][CH2:25][C:26](=[O:27])[C:11]=2[CH:10]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[NH:9]1.Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39].O>CN(C)C=O>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([CH:10]2[N:9]([CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[C:8](=[O:7])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[C:12]3[CH2:24][CH2:25][C:26](=[O:27])[C:11]2=3)=[CH:35][CH:34]=1)#[N:33]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
Cesium carbonate (737 mg, 2.26 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 300 mg, 0.76 mmol) and methyl 2-bromopropionate (252 mg, 1.51 mmol) in N,N-dimethylformamide (10.0 mL), and the mixture is stirred at 50° C. over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is washed twice with water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 160 mg; ESI mass spectrum: [M+H]+=484; Retention time HPLC: 0.85 min (Z018_S04).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:28])[N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:21][CH3:22])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.NCC1C=CN=C(CN(CCCCN(CC)CC)C(=O)OC(C)(C)C)C=1.[F:55][C:56]([F:62])([CH2:60][CH3:61])[C:57](O)=[O:58]>>[F:55][C:56]([F:62])([CH2:60][CH3:61])[C:57]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:28])[N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:21][CH3:22])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH:4]=1)=[O:58]
Reactant: CCC(F)(F)C(=O)O
Reactant: CCN(CCN(C)C)C(=O)CN(Cc1cc(CN)ccn1)C(=O)OC(C)(C)C
Agent: CCN(CC)CCCCN(Cc1cc(CN)ccn1)C(=O)OC(C)(C)C
Product: CCN(CCN(C)C)C(=O)CN(Cc1cc(CNC(=O)C(F)(F)CC)ccn1)C(=O)OC(C)(C)C

Procedure:
By General Procedure Y from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)carbamate (prepared by synthetic route B (analogously to intermediate xii)) and 2,2-difluorobutanoic acid to get the title compound as colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.48 (m, 1H), 7.27 (m, 1H), 7.07 (m, 2H), 4.55 (m, 4H), 4.10 (m, 2H), 3.33 (m, 5H), 2.26 (m, 14H), 1.43 (m, 9H), 1.13 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:6][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:4]([F:32])[CH:3]=1.[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:32])=[C:5]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:6]=2)=[N:10][CH:11]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cn3)c(Cl)cc2F)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c1
Temperature: 90 °C
Yield: 74.2 %

Procedure:
A suspension of N-{4-chloro-2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (2.28 g, 5.01 mmol), calcium chloride (1.23 g, 10.0 mmol) and reduced iron (840 mg, 15.0 mmol) in ethanol (35 mL)/water (5 mL) was stirred with heating at 90° C. for 12 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethyl acetate. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with water (100 mL×2), 5% aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (1.58 g, 74%) as a beige amorphous substance.