Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([C:28]([O:30][CH3:31])=[O:29])[NH:19]1>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the title compound was prepared as a solid (mp=37-40° C). The reaction was monitored by tlc (Rf=0.64 in 10% MeOH/DCM).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([NH2:32])=[O:31]>>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[C:30]([NH:32][C:12]1[CH:13]=[C:8]([CH:4]([CH2:3][CH:2]([CH3:1])[CH3:24])[C:5]([OH:7])=[O:6])[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:26]([F:41])([F:40])[F:25])=[CH:20][CH:19]=2)[CH:11]=1)=[O:31]
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Reactant: NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared by a Buchwald coupling reaction of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with 3,5-bis(trifluoromethyl)-benzamide under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.97 (dd, J=6.60, 2.45 Hz, 6 H), 1.56 (dt, J=13.27, 6.69 Hz, 1 H), 1.75 (ddd, J=13.88, 7.21, 7.03 Hz, 1 H), 2.02 (ddd, J=13.57, 7.70, 7.58 Hz, 1 H), 3.78 (t, J=7.70 Hz, 1 H), 7.47 (s, 1 H), 7.75-7.85 (m, 5 H), 8.08 (s, 1 H), 8.21 (s, 1 H), 8.60 (s, 2 H); Calcd for C28H22F9NO3 (M+H) 592.15, Found 592.1.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)#[C:2][CH3:3].[NH2-].[Li+].[CH3:13][CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18]Br>CS(C)=O>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:1][C:2]#[C:3][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH3:20])[CH3:13]
Reactant: CC#COC1CCCCO1
Reactant: CC(C)CCCCBr
Agent: [Li+]
Agent: [NH2-]
Solvent: CS(C)=O
Product: CC(C)CCCCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(0.5 mole) of prop-1-ynyltetrahydropyranyl ether in 200 ml of dimethyl sulfoxide were added with stirring to a solution of 11.5g. (0.5 mole) of lithium amide in 200 ml of dimethyl sulfoxide. Stirring was continued for 1 hour and 5-methylhexyl bromide 89g. (0.5 mole) were added over 45 min. External cooling was necessary to keep the temperature at 30° C. After 3 hours, the mixture was poured into 1 liter of ice-water. The mixture was extracted with petrol-ether, and the organic phase washed with 10% sulfuric acid, and then water. The solution was dryed over magnesium sulfate concentrated and distilled at 100°-103° C/0.01mm to give 82.6 (70%) of 8-methylnon-2-ynyl tetrahydropyranyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:14][C:13]([C:15](OCC)=[O:16])=[CH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1.[NH3:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:14][C:13]([C:15]([NH2:21])=[O:16])=[CH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccc(OC)cc2)o1
Reactant: N
Solvent: CCO
Product: COc1ccc(-c2cc(=O)cc(C(N)=O)o2)cc1

Procedure:
A mixture of ethyl 6-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (27.4 g), ammonia solution (30%, 50 ml) and ethanol (300 ml) was heated under reflux for an hour. The yellow solid which precipitated on cooling was filtered off and recrystallised from acetic acid-ethanol to yield the title product (mp 303°-308° C. with decomposition).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([NH2:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16]>>[C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[C:22]#[N:23])=[O:16])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)(=[O:11])[NH2:12]
Reactant: NC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(C(N)=O)(CC1)CC2
Yield: 59.5 %

Procedure:
Using 4-aminobicyclo[2.2.2]octane-1-carboxamide (50.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (56.9 mg), the same procedure was followed as in Example 1 to give (2S)-1-[[(4-carbamoylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (47.5 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(F)CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of thionyl chloride of 8.99 g (0.08 mol) was introduced at 20-25° C. into a dry 50 ml round-bottomed flask under a nitrogen atmosphere. Ethyl 3-hydroxy-2-fluoropropionate (10.0 g, 0.07 mol) were subsequently metered in in 1 h and the mixture was subsequently stirred at ambient temperature for a further 2 h. An amount of toluene of 3.98 g (0.04 mol), together with 0.286 g of pyridine (5 mol %), were introduced into a second round-bottomed flask with an Anschutz head and the mixture was heated to 80° C., The mixture from the 1st round-bottomed flask was added dropwise to the preheated solution in 1 h at 75-85° C. Solvents were distilled off under reduced pressure and the residue was subsequently finely distilled at 120° C. and 10 mbar. 4.1 g of distillate were obtained as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[CH:18]3)[CH:10]([NH2:13])[CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[CH:18]3)[CH:10]([NH:13][S:40]([CH:37]2[CH2:39][CH2:38]2)(=[O:42])=[O:41])[CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1
Reactant: CCC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccnc(OC)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NS(=O)(=O)C1CC1)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccnc(OC)c1
Reaction time: 48 h

Procedure:
To a stirred solution of 1-[2-methoxypyridin-4-yl]-1-[(1-pyridin-2-yl-1H-indazol-5-yl)oxy]butan-2-amine (122 mg, 310 μmol) in dichloromethane (11 ml) was added triethylamine (100 μl), followed by cyclopropanesulphonic acid chloride (66 mg, 470 μmol) and DMAP (3.8 mg, 31 μmol). The stirring was continued for 48 h at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 10 mg (6.5%) as a racemic mixture of two diastereomeres.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1>Cl>[CH2:9]([C:7]1[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(CCc2ccccc2)ccn1
Agent: Cl
Product: O=c1cc(CCc2ccccc2)cc[nH]1
Yield: 104.8 %

Procedure:
2-Methoxy-4-phenethylpyridine (22.0 g, 102 mmol) was stirred in concentrated hydrochloric acid (200 mL) at 120° C. for 18 h and then concentrated. The residue was dissolved in MeOH (100 mL) and made basic with aqueous 6 N NaOH and re-concentrated until most of the solvent had been removed. The solids were filtered off, washed with water and dried under vacuum to provide the title compound (21.3 g, 95%) as a beige solid: 1H NMR (500 MHz, DMSO-d6) δ 11.31 (br s, 1H), 7.28-7.21 (m, 5H), 7.17 (t, J=7.1 Hz, 1H), 6.10-6.08 (m, 2H), 2.85-2.82 (m, 2H), 2.70-2.67 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](=O)[CH:12]([CH3:14])[CH3:13]>>[CH:12]([CH:14]1[NH:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:10]1)([CH3:13])[CH3:11]
Reactant: CC(C)C=O
Reactant: NCC(O)c1ccccc1
Product: CC(C)C1NCC(c2ccccc2)O1

Procedure:
2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2-hydroxyethylamine. The ethanolamine was reacted with SOCl2 followed by 2-chloro-4-(trifluoromethyl)phenyl isothiocyanate according to Method C2f to afford 2-(2-chloro-4-(trifluoromethyl)phenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:12](=[O:23])[C:13]1[CH:18]=[C:17]([F:19])[C:16](F)=[C:15]([F:21])[C:14]=1F)=[CH:6][NH:7][N:8]([CH:10]=[O:11])[CH3:9])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:12](=[O:23])[C:13]2[C:14](=[C:15]([F:21])[C:16]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[C:17]([F:19])[CH:18]=2)[N:7]([N:8]([CH3:9])[CH:10]=[O:11])[CH:6]=1)=[O:24])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(N(C)C=O)c2c(F)c(N3CCN(C)CC3)c(F)cc2c1=O
Reaction time: 0.83 h
Yield: 88.3 %

Procedure:
A suspension of 4.92 g (15 mmol) of 3-(2-formyl-2-methylhydrazino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester and 3.41 ml (30.1 mmol) of N-methyl-piperazine in 15 ml of toluene were heated at reflux for 7.5 hours after which a clear, yellow solution was formed. After the addition of further 2.08 ml of N-methyl-piperazine the mixture was heated for 2 hours, cooled and evaporated at 49° C./130 torr. The yellowish oil (13.7 g) was taken up in 30 ml of dichloromethane, washed with 50 ml of water and subsequently twice with each 7.5 ml of half-saturated brine. The aqueous extracts were washed twice with each 15 ml of dichlormethane, the organic phases united, dried over magnesium sulphate, filtered and evaporated at 47° C./20 torr. The crystalline, beige residue (6.1 g) was suspended in 40 ml of tert.-butylmethyl ether, vigorously digested for 50 min., the crystals filtered, washed twice with each 10 ml of tert.-butylmethyl ether and dried at 45° C./13 torr. 5.41 g (88%) of 6,8-difluoro-1,4-dihydro-1-(N-methylformamido)7-(4-methyl- 1-piperazinyl)-4-oxo-3-quinoline-carboxylic acid ethyl ester were obtained as beige crystals of mp 180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.S(O)(=O)(=O)C.S(O)(=O)(=O)C.[NH2:31][NH:32][C:33]([NH2:35])=[NH:34]>>[NH2:35][C:33]1[N:32]=[N:31][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:34]=1
Reactant: N=C(N)NN
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: CS(=O)(=O)O
Product: COc1ccc(-c2nnc(N)nc2-c2ccc(OC)cc2)cc1

Procedure:
Prepared by reacting 4,4′-dimethoxybenzil with aminoguanidine bismesylate using the above procedure. The title compound was obtained as pale yellow plates in 92.5%, mpt=179-181°
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[OH-].[Na+].[CH3:23]OS([O-])(=O)=O>C(O)C.O>[CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([O:20][CH3:23])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
To a solution of estradiol (10.0 g, 36.7 mmol) in ethanol (100 ml) at reflux was added NaOH (100 mmol) in water (10 ml) followed by the dropwise addition of methylsulfate (Me2SO4) (100 mmol). Neutralization with 10% HCl, subsequent concentration of the mixture followed by filtration through silica gel with ethyl ether, afforded 3-methoxyestradiol as white needles. Dissolving metal reduction of 3-methoxyestradiol was carried out via the methods described by Wilds and affording the known dihydroestradiene derivative as a white solid. (See Feiser, L. F., Feiser, M. “Reagents for Organic Synthesis”, John Wiley and Sons, Inc., New York, 1967, pp. v, 583-4, 622-3.)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Yield: 45.1 %

Procedure:
By the procedure outlined in scheme example 929, starting from 4-(aminomethyl)benzoic acid (2.00 g, 13.24 mmol) was treated with sulfuric acid to form methyl 4-(aminomethyl)benzoate (1.20 g, 55%). Methyl 4-(aminomethyl)benzoate (0.600 g, 3.63 mmol) was treated with methanesulfonyl chloride (0.832 g, 7.26 mmol)) in DCM (20 ml) to give crude methyl 4-{[(methylsulfonyl)amino]methyl}benzoate (0.398 g, 45%). Methyl 4-{[(methylsulfonyl)amino]methyl}benzoate (0.398 g, 1.63 mmol) was treated with NaOH and methanol to give 4-{[(methylsulfonyl)amino]methyl}benzoic acid hydrochloride (0.370 g, 98%). The title compound, N-({4-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]phenyl}methyl) methanesulfonamide (0.128 g, 50%) was obtained as a oil from 4-{[(methylsulfonyl)amino]methyl}benzoic acid hydrochloride (0.132 g, 0.461), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1H-enzoimidazole dihydrochloride (0.200 g, 0.39 mmol) and HATU (0.150 g, 0.46 mmol) following the procedure outlined in example 5. ES-LCMS m/z 658 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(F)c4)nc23)CC1
Yield: 76.9 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 mL (0.776 mMol) 3-fluorobenzoyl chloride, 0.100 gm (77.5%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=O.[NH2:12][C:13]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15]>C(Cl)Cl>[CH:16]([C:13]([CH3:19])([N:12]1[C:6](=[O:11])[C:7]2[C:2](=[N:1][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:5])[C:14]#[N:15])([CH3:18])[CH3:17]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: CC(C)C(C)(N)C#N
Solvent: ClCCl
Product: CC(C)C(C)(C#N)N1C(=O)c2cccnc2C1=O
Yield: 74.6 %

Procedure:
To a stirred solution containing 212 g quinolinic anhydride in 950 ml methylene chloride is added to a moderate rate 167 g of 2-amino-2,3-dimethylbutyronitrile. The mixture had reached the boiling point of the solution after about one quarter of the aminonitrile had been added and the rate of addition is adjusted to maintain this temperature. After the addition the solution is heated under reflux for a further 4 hours. The solution is cooled, filtered and concentrated to a thick oil. This oil is dissolved in 950 ml acetic anhydride, 6 g anhydrous sodium acetate added and the mixture distilled until the vapor temperature reached 118° C. when the heating was continued under reflux for 3 hours. The mixture is concentrated in vacuo the residue dissolved in 500 ml toluene and again concentrated. This is repeated. The residue is slurried with a mixture of ether and hexane and the crude product which crystallizes collected (349 g). This is dissolved in 700 ml methylene chloride and filtered through a column containing 700 g silica gel and the product eluted with methylene chloride. Concentration of the eluant gave 258 g of the desired product. An analytically pure sample with mp 95°-96° C. can be obtained by the recrystallization of the product from ether-methylene chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10]2
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CC1(C)CCc2cc(C=C3C(=O)Nc4ccc(Br)cc43)ccc2O1

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].[CH3:14][CH2:15]O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:14]=[CH:15][N:8]=[C:4]2[CH:3]=1
Reactant: CCO
Reactant: Nc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccn2ccnc2c1

Procedure:
4-Chloro-pyridin-2-ylamine (1 eq, 38.9 mmol, 5 g) is added to a solution of chloroacetic aldehyde (3 eq, 117 mmol, 15.1 ml) in EtOH (60 ml). NaHCO3 (2 eq, 77.8 mmol, 6.53 g) is added and the reaction mixture is heated at reflux for 17 h. The solvent is removed in vacuo and the product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 7-chloro-imidazo-[1,2-a]-pyridine as a red solid; [M+H]+=153
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].O.[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:18]([NH:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCC(=O)C(N)C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)C(NC(=O)C=Cc1ccccc1)C(=O)OC

Procedure:
Sodium hydrogen carbonate (10.0 g) was added to a mixture of methyl 2-amino-3-oxovalerate hydrochloride (9.1 g), ethyl acetate (50 ml) and water (40 ml) with ice-cooling and stirring followed by dropwise addition of a solution of cinnamoyl chloride (8.3 g) in ethyl acetate (10 ml). The whole mixture was stirred under ice-cooling for 2 hours and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and isopropyl ether was added to the residue to give methyl 2-cinnamoylamino-3-oxovalerate as crystals; yield 8.8 g (63.8%). Recrystallization from ethanol gave colorless needles melting at 119°-120° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]1=[O:33])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:18][C:14]1[CH:13]=[C:12]([CH:11]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]2=[O:33])[CH2:10][CH2:9][OH:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(C(CCO)c2cccc(F)c2)c2ccccc2C12CCCCC2
Reaction time: 1 h
Yield: 83.9 %

Procedure:
1′-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]spiro-[cyclohexane-1,3′-indol]-2′(1′H)-one (0.85 g, 1.82 mmol) was dissolved in tetrahydrofuran and tetrabutyl ammonium fluoride (1.0 M in THF, 3.64 mL, 3.64 mmol) was added and the mixture was stirred for 1 hour. Reaction was quenched with saturated aqueous ammonium chloride then saturated sodium bicarbonate was added, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate in hexane) to afford 0.54 g (84%) racemic 1′-[1-(3-fluorophenyl)-3-hydroxypropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one that was resolved by chiral HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH:23][C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:23]([CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)[C@@H:24]([CH3:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:6]
Reactant: COc1ccc(CCN[C@@H](C)Cc2ccccc2)cc1OC
Reactant: O=C(Cl)c1cccc(Br)c1
Product: COc1ccc(CCN(C(=O)c2cccc(Br)c2)[C@@H](C)Cc2ccccc2)cc1OC

Procedure:
The title compound was prepared from 3-bromobenzoyl chloride and (S)-[2-(3,4 dimethoxyphenyl)ethyl]-(1-methyl-2-phenylethyl)amine D8 according to a procedure similar to that for Example 76.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1F
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Commercially available 2-fluorobenzoic acid (75 g, 0.54 Mol) was added to chlorosulphonic acid (320 g) over 15 minutes, stirred for 30 minutes then heated to 90° C. for 4½ hrs. Once cool, the reaction was quenched onto ice/water (1.5 kg/324 ml) and granulated for 1 hr. The precipitated product was filtered, water washed and dried at 50° C. under vacuo to give the title compound (99.7 g, 78.1%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A79) and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.