Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Br[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>[Ni]>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:12]2[N:13]=[N:14][N:10]([C:2]([CH3:1])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:3])[N:11]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2)n1
Agent: [Ni]
Product: COC(=O)c1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1

Procedure:
reacting the ortho-transmetalated 2-(1-methyl-1-phenylethyl)-5-phenyl-2H-tetrazole with methyl 4-bromobenzoate in the presence of phosphinated nickel catalyst to give 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carboxylic acid methyl ester,
Reaction SMILES: [CH2:1]([CH:8]([C:14](=O)[CH3:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)C>[NH2:24][C:22]1[N:23]=[C:9]([OH:10])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([CH3:15])[N:21]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: O=C(O)O
Solvent: CCO
Product: Cc1nc(N)nc(O)c1Cc1ccccc1

Procedure:
A mixture of ethyl 2-benzyl-3-oxobutanoate (6 g, 27.2 mmol), guanidine carbonate (2.94 g, 16.3 mmol) and ethanol (20 ml) was refluxed for 10 hours. After cooling, the precipitate was filtered and washed with water, ethanol and ether in order, to the object compound (3.62 g, 61.7%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([O:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]5[C:44](=[O:45])[N:43]([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[N:42]([CH3:52])[C:41]=5[CH3:53])=[O:39])=[CH:33][C:32]=4[F:54])=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:55].CCOC(C)=O>C(OCC)(=O)C>[ClH:55].[NH2:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([O:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]5[C:44](=[O:45])[N:43]([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[N:42]([CH3:52])[C:41]=5[CH3:53])=[O:39])=[CH:33][C:32]=4[F:54])=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)[CH2:14][CH2:15]1)=[O:11]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(OC(=O)CN)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To the mixture of 1-(3-(4-(4-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)quinolin-7-yloxy)propyl)cyclopropyl 2-(tert-but-oxycarbonylamino)acetate (160 mg, 0.216 mmol) in 8 mL of ethyl acetate was added a solution of HCl/EtOAc (0.93 mol/L, 5 mL) dropwise. The reaction mixture was stirred at rt for 30 minutes and then filtered. The solid was washed with ethyl acetate (10 mL×2) to afford the title compound as a white solid (55 mg, 37.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)[C:20]1[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[N:24][CH:25]=1)=[O:6]
Reactant: NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=407.1, tR (minutes, Method F)=2.25
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([CH:28]=[CH2:29])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate and tributyl(vinyl)stannane, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:26]>>[NH2:26][C:9]1[C:10]([F:20])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:12]=[C:13]2[C:8]=1[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)c(F)c2c1=O
Product: Nc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
1-Cyclopropyl-5,6-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 28% aqueous ammonia were heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in a 1N aqueous solution of sodium hydroxide, and neutralized with a 10% aqueous solution of acetic acid. The crystals which precipitated were collected by filtration to give 5-amino-1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 214°-216° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=O)[CH2:10][CH3:11].C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:4][CH:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])[CH2:3][CH2:2]1
Reactant: CCC(=O)c1ccncc1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(NC1CC1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a mixture of 8 g of molecular sieves and 8.4 g (148 mmol) of cyclopropylamine in 100 ml of methanol at 0° C., were successively added 11 ml of acetic acid and 10 g (74 mmol) of 4-propionyl-pyridine. The reaction mixture was stirred for 3 hrs at reflux and cooled to room temperature. A solution of 6.9 g (185 mmol) of sodium cyanoborohydride in 20 ml of methanol was added dropwise. The reaction mixture was stirred for 3 hrs at reflux, and cooled to room temperature. The reaction mixture was concentrated in vacuum to half its volume and diluted with 80 ml of dichloromethane. Heptane was added so that a solid precipitated. The solid was filtrated. The filtrate was concentrated in vacuum to give 8.7 g (66%) of N-cyclopropyl-1-pyridin-4-yl-propylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15](=[O:16])[N:14]3[CH:10]([CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13]3)[C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.ClC1C=CC(C2C(=[O:44])N3C(=CC(C)(C)C3)C=2C2C=CC=CC=2)=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15](=[O:16])[N:14]3[C:10]([OH:44])([CH2:11][C:12]([CH3:17])([CH3:18])[CH2:13]3)[C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC2C(c3ccccc3)=C(c3ccc(Cl)cc3)C(=O)N2C1
Reactant: CC1(C)C=C2C(c3ccccc3)=C(c3ccc(Cl)cc3)C(=O)N2C1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)CN2C(=O)C(c3ccc(Cl)cc3)=C(c3ccccc3)C2(O)C1

Procedure:
It was not possible to observe the 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,6,7,7a-tetrahydro-pyrrolizin-3-one (keto tautomer of 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-ol) expected as a hydrolysis product in any case. After relatively long standing (16 h) of a CHCl3 solution of the product, the 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,6-dihydropyrrolizin-3-one described in example 29 is obtained as a substance in pure form (H2O elimination).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 76.6 %

Procedure:
Using general procedure A, methyl 4-aminobenzoate (380 mg, 2.51 mmol) and 1-Boc-4-piperidone (500 g, 2.51 mmol) afforded 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (643 mg, 77%).
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:10]3[C:11]=2[C:6](=[CH:7][CH:8]=[CH:9]3)[C:5](=[O:16])[O:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:1]([CH:3]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:10]3[C:11]=2[C:6](=[CH:7][CH:8]=[CH:9]3)[CH:5]([OH:16])[O:4]1)[CH3:2]
Reactant: CCC1OC(=O)c2cccc3cccc1c23
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: ClCCl
Product: CCC1OC(O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a solution of 3-ethylbenzo[de]isochromen-1 (3H)-one (0.55 g) in dichloromethane (7 mL) at −78° C. was added diisobutylaluminum hydride (2.19 mL, 20% solution in toluene). After 3 hours 10% solution aqeuous solution of citric acid (10 mL) was added and the mixture was stirred for 15 minutes at room temperature. Phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine, dried with Na2SO4 and concentrated. The purification of evaporation residue by column chromatography (ethyl acetate-heptanes) afforded 3-ethyl-1,3-dihydrobenzo[de]isochromen-1-ol (0.22 g, mixture of diastereomers) that was dissolved in dichloromethane (5 mL). Solution was cooled to 0° C. and trimethylsilyl cyanide (0.39 mL) was added, followed by boron trifluoride triethyl etherate (0.26 mL). After 2.5 hours saturated solution of NaHCO3 (10 mL) was added and the mixture was extracted with dichloromethane. Combined organic phases were washed with brine, dried (Na2SO4) and concentrated. The evaporation residue containing the mixture of diastereomers of 3-ethyl-1,3-dihydrobenzo[de]isochromene-1-carbonitrile (170 mg) was mixed with dioxane (2 mL) and 10% aqueous solution of NaOH (1.6 mL) was added and the mixture was heated to reflux. After 13 hours, reaction mixture was cooled to room temperature and water (10 mL) and dichloromethane (10 ml) were added. Aqueous phase was acidified with 4M HCl and extracted with EtOAc (3×10 mL). Combined organic phases were washed with brine, dried with Na2SO4 and concentrated. The evaporation residue containing the 3-ethyl-1,3-dihydrobenzo[de]isochromene-1-carboxylic acid (80 mg) was turned to the title compound using synthesis methods A2 and A3 along with the separation method E in A3. The obtained 2-(3-ethyl-1,3-dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazole was converted to the title compound using salt formation method A. (Yield 5.7 mg).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[OH:26].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].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.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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([Cl:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(O)c(Cl)c4)cc3CC[C@@H]12
Yield: 60.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-chloro-4-hydroxyphenylboronic acid (134 mg, 0.7 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 139 mg (61%) of the title compound as a white solid. mp 245°. FDMS: m/e=355. α[D]589 =+17.62 (c=1.02, chloroform).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][CH:72]=1)[NH2:69]>C(Cl)Cl>[Cl:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-chloro-aniline (Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 48 mg.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=1)[O:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]2[CH2:27][CH:26](S(C)(=O)=O)[CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(#N)C>[CH:23]([N:24]1[CH2:27][CH:26]([N:2]([C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[O:5][CH3:6])[CH3:1])[CH2:25]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNc1ccccc1OC
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N(C)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 25.9 %

Procedure:
To a solution of 0.65 g of N-methyl o-anisidine in 15 mL of acetonitrile, was added 0.280 g of K2CO3, followed by 0.650 g of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction mixture was heated at 80° C. for 1 h then at 50° C. overnight. Water was added and the mixture was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The product was filtered through 100 mL of silica gel, eluting a with 15% ethyl acetate/hexanes then 25% ethyl acetate/hexanes to give 0.200 g of the desired product: mp 91-95° C. MS (ES) m/z (relative intensity): 356 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: CC#N
Reactant: O=Cc1cc(Br)ccc1Cl
Product: N#CCC(O)c1cc(Br)ccc1Cl

Procedure:
Alkylation of 5-bromo-2-chlorobenzaldehyde with acetonitrile following the method used in Example 114 gave 3-(5-bromo-2-chlorophenyl)-3-hydroxypropanenitrile as a pale yellow liquid. Yield (4.42 g, 75%): 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=2.8 Hz, 1H), 7.53 (dd, J=8.8, 2.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.30 (d, J=4.8 Hz, 1H), 5.13-5.09 (m, 1H), 2.96 (ABd, J=16.8, 4.8 Hz, 1H), 2.83 (ABd, J=17.0, 6.0 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Si](OS(C(F)(F)F)(=O)=O)([C:22](C)(C)[CH3:23])(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH2:11][CH2:22][CH3:23])([CH3:7])[CH3:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 96 %

Procedure:
Compound 9t was synthesized by a procedure similar to that described for 9a using 3-chloropentaphenone (8k, 2.7 g, 0.014 mol), TBDMSOTf (3.5 mL, 15 mmol), and Et3N (3.1 mL) in CH2Cl2 (25 mL). After purification, 4.18 g (96%) of the title product was isolated as colorless oil: 1H NMR (CDCl3) δ 7.47-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.30-7.28 (m, 1H), 7.25-7.22 (m, 1H), 5.18 (t, 1H, J=7.2 Hz), 2.20 (q, 2H, J=7.5 Hz), 1.54-1.38 (m, 2H), 1.02 (s, 9H), 1.00-0.90 (m, 3H), −0.05 (s, 6H); 13C NMR (CDCl3) δ 148.0, 141.8, 133.9, 129.2, 127.6, 125.9, 123.9, 113.0, 28.3, 25.8, 22.8, 14.0, 0.0, −4.01. C17H27ClOSi.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1C=CC(S(O)(=O)=O)=C[CH:13]=1.C>CC(C)=O>[C:8](=[C:2]([CH:3]([CH2:5][OH:6])[OH:4])[OH:1])([CH3:13])[CH3:7]
Reactant: OCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)=C(O)C(O)CO
Reaction time: 24 h

Procedure:
Freshly distilled glycerol (10 g, 0. 11 mole) was shaken until dissolved with 65 mL of dry acetone containing 1 g of TsOH. After 24 hr. the solution was neutralized first with PbCO3 and afterwards with Ag2CO3, warmed with charcoal, and shaken with a large excess of CaCI2 overnight. The supernatant liquid was then filtered. The solvent was removed by rotary evaporation, and the product fractionated under diminished pressure, giving 9.5 g of the main fraction (b.p. 105-106° C./25 mm) Y=65.4%. NMR: 1H: δ (ppm) 4.14-4.16 (m,1H, CH), 3.65-4.0 (qxd, 2H, CH2),3.57 (m, 2H, CH2OH), 2.05 (sb. 1H,OH), 1.40, 1.33 (CH3); 13C: δ (ppm) 109.4 (COO), 76.1 (CH), 65.7 (CH2O), 62.8 (CH2OH), 26.6, 25.2 (CH3).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)([OH:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:35]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][C:20]([O:23][CH3:35])([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
60% sodium hydride (0.225 g, 5.2 mmol) was added to an N,N-dimethylformamide solution (20 ml) of 1-(4-benzyloxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (2 g, 4.7 mmol) and iodomethane (0.585 ml, 9.4 mmol) under an argon atmosphere while ice cooling, followed by stirring at the same temperature. After 2 hours, the mixture was poured into ice water, and the precipitate was collected by filtration. The resulting solid was dissolved in ethyl acetate/dichloromethane and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=100:0→95:5) to afford the title compound as a white powder (1.64 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH:16]1([N:15]([CH3:14])[C:2]2[C:3]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNC1CCCCC1
Reactant: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(c1ccnc2[nH]cc([N+](=O)[O-])c12)C1CCCCC1

Procedure:
To a suspension of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (57 mg) in 2-propanol (180 μl) were added N-methylcyclohexanamine (154 μl) and N,N-diisopropylethylamine (50 μl), and irradiated microwave at 120° C. for 15 minutes. The reaction mixture was purified by flash column chromatography over silica gel with a EtOAc/methanol (100:0-60:40) as eluant. then by preparative silica gel thin-layer chromatography with EtOAc as eluant to give a solid. The solid was washed with diisopropyl ether to give N-cyclohexyl-N-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (7.9 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyridine (example E.32) (0.075 g, 0.20 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.051 g, 0.2 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 45%). MS (ISP) 373.2 [(M+H)+] and 375 [(M+2+H)+]; mp 197-199° C.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].Br[CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C1C=CC=CC=1>[CH:18]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=1)[C:14]#[N:15])([CH3:20])[CH3:19]
Reactant: N#CCc1ccc(OC(F)(F)C(F)F)cc1
Reactant: CC(C)Br
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)C(C#N)c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
A mixture of 39.85 g (0.171 mol) of p-(1,1,2,2-tetrafluoroethoxy)phenylacetonitrile, 3.71 g (9.96 mmol, 5.8 mol %) of dicyclohexyl-18-crown-6, 22.0 ml (28.8 g, 0.234 mol) of 2-bromopropane, 55 ml of benzene, and 55 ml of 50% sodium hydroxide is stirred for 45 minutes during which there is an exotherm from 25° C. to 43° C. The reaction mixture is then heated at 45° C. for 16.5 hours. After dilution with 200 ml of water, the reaction mixture is extracted with 200 ml of ether. The ether solution is washed with 400 ml of 12% hydrochloric acid, 200 ml of 5% hydrochloric acid, and 300 ml of water. The ether solution is dried with sodium sulfate, filtered, and then evaporated to give 47.13 g of an oil. This oil is vacuum distilled to give 34.83 g (74%), boiling point 83° C. to 85° C. at 0.055 to 0.090 mm Hg.