Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([OH:10])=O)[CH2:4][CH:5]([CH3:7])[CH3:6].CN(C)[C:13]1C=CC=[C:19]2[C:14]=1[CH:15]=CC=C2S(Cl)(=O)=O.[C:28](=O)([OH:30])[O-:29].[Na+]>CC(C)=O>[C:28]([NH:2][C@H:3]([CH:8]=[O:10])[CH2:4][CH:5]([CH3:6])[CH3:7])([O:30][C:14]([CH3:19])([CH3:15])[CH3:13])=[O:29]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 37 °C
Reaction time: 0.5 h

Procedure:
This material (130 mg, 0.562 mmol) was dissolved in ethyl acetate (2 ml). The solution was cooled to 0° C., saturated with HCl (g) and stirred 15 min. Evaporation of the solvent in vacuo gave an oil which was repeatedly evaporated in vacuo with ethyl acetate until a white solid precipitated. Filtration gave leucine-HCl (75 mg) which was dried in vacuo at room temperature. This hydrochloride (10 μg, 0.06 μmol) in 100 μl of 0.2 M sodium bicarbonate buffer, pH 9.0, was treated with 100 μl of a 0.02 M solution of 5-dimethylaminonaphthalene-1-sulfonyl chloride in acetone. The mixture was stirred at 37° C. for 30 min and quenched with 0.1 ml of formic acid. The mixture was evaporated to dryness under a stream of nitrogen and the residue dissolved in methanol (0.5 ml). The solution (10 μl) was analyzed by HPLC using as the mobile phase a solution of arginine (5 mM), copper sulfate.5H2O (2.5 mM) and ammonium acetate (5 mM) in glass distilled water, adjusted to pH 7.8 with NH4OH. Fluorescence at 520 nm was monitored with excitation at 340 nm. Samples were run in duplicate, and authentic samples of D- and L-leucine were used as controls. The observed L- to D-ratios along with measured optical rotations of the leucine HCl samples are summarized below.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(SCCCOC3C=C(C=CC=3)C#N)=N2)C=CC=CC=1.[C:38]1([C:44]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[N:45]2[CH:49]=[N:48][C:47]([S:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][C:56]3[CH:57]=[C:58]([CH:61]=[CH:62][CH:63]=3)[C:59]#[N:60])=[N:46]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:64]1([C:44]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:45]2[CH:49]=[N:48][C:47]([S:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][C:56]3[CH:57]=[C:58]([CH2:59][NH2:60])[CH:61]=[CH:62][CH:63]=3)=[N:46]2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: N#Cc1cccc(OCCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: N#Cc1cccc(OCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: NCc1cccc(OCCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 7 and using, instead of 3-[(3-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}propyl)oxy]benzonitrile, 3-[(4-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}butyl)oxy]benzonitrile obtained in Reference Example 10, the title compound was obtained as a yellow oil (8.65 g, 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: Cc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)nc1

Procedure:
2-Bromo-5-methylpyridine (1.29 g, 7.5 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (3.8 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from toluene/isohexane, gave 3-(5-methylpyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 10.48 (1H, d, J 7), 8.50-8.52 (1H, m), 8.46 (1H, s), 7.72 (1H, d, J 8), 7.61-7.65 (1H, m), 7.31 (1H, d, J 7); m/z (ES+) 279 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].[CH2:20](OC(OCC(C)(C)C)N(C)C)[C:21](C)(C)[CH3:22].OCC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[N:40]1[CH:39]=[CH:44][C:43]([CH2:20][CH2:21][CH2:22][O:13][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])=[CH:42][CH:41]=1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: OCCc1ccccn1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)OCCCc1ccncc1

Procedure:
In analogous manner [o-(2,6-dichloro-anilino)-phenyl]-acetic acid-2-(2-pyridyl)-ethyl ester with a melting point of 67°-68°C (crystallisation from petroleum ether) is obtained starting from 2.96 g of [o-(2,6-dichloro-anilino)-phenyl]-acetic acid, 3.0 g of dimethyl formamide-dineopentylacetal, and 1.4 g of 2-(2-hydroxyethyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[BH4-].[Na+]>ClCCl.CO.O>[NH2:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1cc(CO)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixed solution of this aldehyde (745 mg, 3.63 mmol) in dichloromethane (5 ml) and methanol (10 ml) was added sodium borohydride (280 mg, 7.40 mmol) with ice-cooling and stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium hydrochloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; hexane:ethyl acetate=6:1 2:1) to provide 736 mg (yield 98%) of 4-amino-3,5-diisopropylbenzenemethanol as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:13]([OH:15])=[O:14].O>CCCCCC>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]2[C:5]([O:15][C:13](=[O:14])[C:3]=12)=[O:7]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: CCCCCC
Solvent: O
Product: O=C1OC(=O)c2c(F)c(F)cc(F)c21
Temperature: 25 °C

Procedure:
A 25 mL round-bottom flask equipped with a Barrett trap and a condenser was charged with 1.00 g of 3,4,6-trifluorophthalic acid and 15 mL of mixed xylenes under a dry nitrogen atmosphere. The reaction mixture was then heated under reflux with azeotropic removal of water for 5 hr. and was then cooled to room temperature. After the addition of 20 mL of hexane the mixture was cooled in an ice bath. The solvent was then removed on a rotary evaporator to afford 3,4,6-trifluorophthalic anhydride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>>[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:21][C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[CH2:17][CH2:18]3)[C:6]=2[CH:5]=1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Product: N#Cc1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (282 mg, 75%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (333 mg, 0.98 mmol) and 3-(bromomethyl)benzonitrile (191 mg, 0.98 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.68 (s, 1H), 7.57 (d, 2H), 7.43 (t, 1H), 7.00 (s, 1H), 4.88 (d, 1H), 4.20 (m, 1H), 3.56 (s, 2H), 2.85 (d, 2H), 2.25 (dt, 2H), 2.12 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C19H19ClN5S, 384.1; Observed: 384.2 (M++1).
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1([CH3:13])[CH3:12])=[O:4].[H-].[Na+].CC1C=CC(S(O[C:27](=[CH:32][C:33]#[N:34])[C:28]([F:31])([F:30])[F:29])(=O)=O)=CC=1>CN(C=O)C>[NH2:34][C:33]1[CH:32]=[C:27]([C:28]([F:31])([F:30])[F:29])[O:1][C:2]=1[C:3]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1([CH3:13])[CH3:12])=[O:4]
Reactant: CC1(C)C(=O)NCCN1C(=O)CO
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NCCN1C(=O)c1oc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
4-(2-Hydroxyacetyl)-3,3-dimethylpiperazin-2-one (0.090 g, 0.48 mmol) and sodium hydride (60%, 0.040 g, 0.97 mmol) were dissolved in 3 mL DMF and stirred at 25° C. for 30 min. To the resulting, cooled (0° C.) mixture was added drop-wise 3-cyano-1,1,1-trifluoroprop-2-en-2-yl 4-methylbenzenesulfonate (0.16 g, 0.56 mmol). The reaction was gradually warmed up to 25° C., stirred for an additional 2 hours, 2 additional equivalents of sodium hydride were added and the mixture stirred for another additional 4 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried, the solvent eliminated under vacuum and the crude product purified by preparative thin layer chromatography. (silicagel, dichloromethane:methanol 95:5) to afford 0.010 g of 4-(4-amino-2-(trifluoromethyl)furan-5-carbonyl)-3,3-dimethylpiperazin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCN1CCC(CN)C1
Product: CCN1CCC(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and (1-ethylpyrrolidin-3-yl)methanamine (12.8 mg, 0.1 mmol). The title compound was obtained as a solid (10.7 mg, 23% yield). MS ink: 460.87, 462.87 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[C:15](Cl)(=[O:17])[CH3:16]>CN(C=O)C>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)(=[O:17])[CH3:16]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
AlCl3 (303g, 2.27 mol) is placed in a 3-necked flask fitted with a thermometer and a dropping funnel. While stirring DMF (50 ml) is added dropwise and the temperature rises to about 60°. The mixture is cooled down to 45°, and oxindole (33 g, 0.25 mol) is added in 3 portions. After an additional 10 minutes, acetyl chloride (36 ml, 0.5 mol) is added. The mixture is stirred for an additional 30 minutes at room temperature. The mixture is poured onto ice (3000 g). This results in the formation of a solid which is filtered off, washed first with water and then with cold methanol (1000 ml), and then dried to give 5-acetyloxindole.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C.O>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:22][C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 600 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 10 ml of DMF were added 500 mg of tert-butyl (3S)-3-aminopiperidine-1-carboxylate, 518 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, and 366 mg of 1-hydroxybenzotriazole, followed by stirring overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 808 mg of tert-butyl (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1.[O:23]1[CH2:28]COCC1.[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH3:38])[C:32]=1B(O)O)[CH3:30].C([O-])([O-])=O.[K+].[K+]>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.O.CCOC(C)=O>[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH3:38])[C:32]=1[C:2]1[N:7]=[C:6]([O:23][CH3:28])[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1)[CH3:30]
Reactant: Cc1nc(Cl)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(OC)n1
Temperature: 25 °C

Procedure:
To a sealed tube containing (1S)-(2,4-dichloro-6-methyl-pyrimidin-5-ylmethyl)methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (3.4 g, 10.25 mmol) is added dioxane (40 mL), 2,6-diethylphenylboronic acid (3.65 g, 2.0 eq., 20.5 mmol) and K2CO3 (5.7 g, 4.0 eq., 41 mmol dissolved in 10 mL water) under a nitrogen atmosphere. Pd(PPh3)4 (5 mol %, 590 mg) is added and after sealing is allowed to react at 95° C. for 16 h. After cooling to room temperature, EtOAc (100 mL) and water (100 mL) is added and the organic layer is washed with sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. The crude sample is purified by SiO2 flash chromatography using hexanes:Et2O 5:1 with 1.0% triethylamine to recover the title compound as a colorless oil. [mass expected (429.60); mass found (429.33)]
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.O1CCOCC1.[NH3:34]>O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:34])=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1
Reactant: N
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.2 g. (31.5 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride and 150 ml. dioxan, there is added dropwise, while stirring at ambient temperature, within the course of 30 minutes, a solution of 100 ml. concentrated aqueous ammonia in 50 ml. dioxan. The reaction mixture is stirred for a further 30 minutes and then sufficient water is added thereto to precipitate out the desired amide. After suction filtration, drying and recrystallisation from toluene, there are obtained 8.5 g. (75% of theory) of amide; m.p. 170°-173° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([O:30][Si](C)(C)C)=[C:27]([CH3:29])[CH3:28]>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:27]([CH3:29])([CH3:28])[C:26]([O:25][CH3:24])=[O:30])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(C)(C)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Yield: 97.7 %

Procedure:
To 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-ol (125 mg, 0.40 mmol) in 5 mL of DCE was added TiCl4 (0.44 mmol; 0.44 mL of 1 M solution in DCM). A precipitate immediately formed. The reaction was concentrated in vacuo to approx 1 mL volume and treated with 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.23 mL, 1.2 mmol) and the reaction became homogeneous and was complete. The reaction was quenched with NaHCO3, extracted 4× EtOAc, and combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography using 25% EtOAc in hexanes to give methyl 2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanoate (155 mg, 99%). MS found: (M+H)+=397.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17](CC3(C4C=CC=CC=4)CC3C3C=CC=CC=3)=O)[CH2:9][CH:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][O:36]/[N:37]=[C:38](\[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][O:49][NH2:50])/[C:39]([O-:41])=[O:40].[C:51]1(C)C=CC=CC=1>>[C:1]1([C:7]2([C:16](=[N:50][O:49][CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3/[C:38](=[N:37]\[O:36][CH3:35])/[C:39]([O:41][CH3:51])=[O:40])[CH3:17])[CH2:9][CH:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO/N=C(/C(=O)[O-])c1ccccc1CON
Reactant: O=C(CC1(c2ccccc2)CC1c1ccccc1)CC1(c2ccccc2)CC1c1ccccc1
Reactant: Cc1ccccc1
Product: CO/N=C(/C(=O)OC)c1ccccc1CON=C(C)C1(c2ccccc2)CC1c1ccccc1

Procedure:
To a 50 ml round bottom flask equipped with magnetic stirrer and reflux condenser was charged the 0.8 g (0.0034 moles, 1.0 eq.) of 1,2-diphenylcyclopropylmethyl ketone 50 mls of anhydrous toluene, approximately 20 4A molecular sieves, and 0.9 g (0.0037 moles, 1.1 eq.) of (E)-2-(aminooxymethyl)phenylglyoxylate O-methyloxime. The reaction was refluxed for a total of 2.5 hours, then cooled, and filtered through filter paper to remove the insoluble material. The filtrate was poured into 100 mls of water and extracted with 3×50 mls of ether. The ether extract was then washed with 2×100 mls of water, 100 mls of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator to afford 1.4 g of a thick amber liquid which was chromatographed on silica gel with 20% ethyl acetate, 80% hexane. The pure fractions were combined and concentrated on a rotary evaporator to afford 460 mg of a thick clear colorless oil (30% isolated yield) consistent with the desired product, (E)-Methyl 2-[2-((((1-(1,2-diphenylcyclopropyl)ethylidene)amino)-oxy)methyl)phenyl]-2-methoxyiminoacetate upon analysis by 300 MHz 1H NMR.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=O)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+:29](C)C.C(N(CC)C(C)C)(C)C.N>C(#N)C>[NH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[NH:8][CH:7]=[C:6]([C:4]([NH2:29])=[O:3])[CH:10]=2)=[N:12]1
Reactant: CN(C)C(F)=[N+](C)C
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.35 mmol) (from Example 11) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (92.7 mg, 0.35 mmol) (Aldrich, Milwaukee, Wis.) in acetonitrile (6 mL) at 0° C. was added N,N-diisopropylethylamine (DIPEA) (54.28 mg, 0.42 mmol). The mixture was allowed to warm up to room temperature and stirred for one hour. The mixture was then cooled in an ice-bath and charged with ammonia gas. After stirring at room temperature for overnight, the reaction was concentrated, diluted with water and extracted with DCM. The organic layer was concentrated and triturated with DCM to give the titled compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2c(c3cc(OCc4ccccc4)ccc3n2Cc2ccccc2)C1
Temperature: 10 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A mixture of intermediate (1) (0.09 mol) in N,N-dimethylformamide (200 ml) was stirred at 10° C. under a N2 flow. Sodium hydride (60%; 0.1 mol) was added portionwise. The mixture was stirred for 1 hour at room temperature, then it was cooled to 5° C. Benzylbromide (0.1 mol) was added dropwise. Stirring was continued for 2 hours. The mixture was cooled to 10° C. and poured out into cold water (500 ml). This mixture was extracted with CH2Cl2 (2×250 ml). The separated organic layer was washed with water (100 ml), dried, filtered and the solvent was evaporated. The solid residue was washed with CH3CN (50 ml), cooled and the resulting precipitate was filtered off and dried, yielding 30.0 g (76%) of ethyl 1,3,4,5-tetrahydro-8-(phenyl-methoxy)-5-(phenyl-methyl)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 2).
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][C:7]#[N:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[CH3:15][C:16]1(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.S(=O)(=O)(O)[OH:25]>C(O)(=O)C>[CH3:15][C:16]1([NH:8][C:7](=[O:25])[CH2:6][N:5]2[C:4](=[O:9])[C:3]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]3[C:1]2=[O:14])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(O)O
Reactant: CC1(O)CCCCCC1
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Product: CC1(NC(=O)CN2C(=O)c3ccccc3C2=O)CCCCCC1

Procedure:
By processes similar to those described in Examples 1, 2 and 3, phthalimidoacetonitrile (27.9 g.) was caused to react with 1-methylcycloheptan-1-ol (24 g.) in glacial acetic acid solution (90 ml.) at 50° C. by the addition of concentrated sulphuric acid (0 ml.). After the initial vigorous reaction, a further 6 ml. of sulphuric acid wasadded. After 2 hours the resulting N-(1-methylcycloheptyl)-2-phthalimidoacetamide was isolated by pouring into water; it was collected, washed and dried before crystallisation frombenzene; it was obtained as a colourless crystalline solid, m.p. 190° C.