Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[OH:22])[C:15]([O:17][CH3:18])=[O:16])=[O:11])[CH2:7]1)[CH3:2].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:30][CH:29]=1>>[CH:38]1([CH2:37][CH2:36][CH2:35][O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][O:22][C:21]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[C:10]([N:8]3[CH2:7][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:9]3)=[O:11])=[CH:29][CH:30]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: BrCCCc1ccc(OCCCC2CCCCC2)cc1
Reactant: CCOC(=O)CC1CN(C(=O)c2cc(C(=O)OC)ccc2O)C1
Product: CCOC(=O)CC1CN(C(=O)c2cc(C(=O)OC)ccc2OCCCc2ccc(OCCCC3CCCCC3)cc2)C1

Procedure:
Preparation takes place in analogy to the process described in Example 22 from methyl 3-{[3-(2-ethoxy-2-oxoethyl)azetidin-1-yl]carbonyl}-4-hydroxybenzoate and 1-(3-bromopropyl)-4-(3-cyclohexylpropoxy)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S1(=O)CCC(COS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
421 mg (1.13 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 500 mg (1.69 mmol) of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl trifluoromethanesulphonate and 1.46 ml (1.46 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 15 ml of THF were reacted according to General Method 7B. Aqueous work-up gave the title compound. Yield: 862 mg (purity 91%, quant.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:14]([SiH2:18][O:19][C:20]([CH3:30])([CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[C:22]=1[NH2:28])([CH3:17])([CH3:16])[CH3:15].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>CN(C=O)C>[NH2:28][C:22]1[C:21]([C:20]([CH3:30])([CH3:29])[O:19][SiH2:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:27][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(N)c1N
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
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: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(NC(=O)c2n[nH]c3ncc(Br)cc23)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (1.0 g, 4.13 mmol) and 3-(tert-butyl-dimethyl-silanyloxymethyl)-benzene-1,2-diamine Compound 6a (1.05 g, 4.17 mmol), HATU (1.58 g, 4.16 mmol) and DIPEA (2.5 mL, 35.9 mmol) in DMF (50 mL) was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), then sequentially washed with hydrochloric acid (20 mL, 1M), water (30 mL×3) and brine (20 mL). The organic solution was evaporated to dryness in vacuo and purified by silica gel chromatography (10% to 50% of ethyl acetate in hexanes) to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid [2-amino-3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-amide Compound 6b (1.21 g, 61% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=2.1 Hz), 8.73 (s, 1H), 8.67 (d, 1H, J=2.1 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=7.2 Hz), 6.83 (t, 1H, J=7.2 Hz), 4.78 (s, 2H), 0.95 (s; 9H), 0.11 (s, 6H); MS (ESI) m/z: 477 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:24])[C:10](OC(=O)C)=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-:27].[K+].[K+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:27])=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(C=C(OC(C)=O)C(=O)NC2CCC(C)(C)CC2)c1
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)NC2CCC(C)(C)CC2)ccc1O
Yield: 93 %

Procedure:
Using 8.99 g of N-(4,4-dimethylcyclohexyl)-acetoxy-3-methoxycinnamamide (Example 63), 100 ml of methanol, and 10 g of potassium carbonate, a reaction similar to that conducted in Example 54 was carried out. As a result, 7.34 g of N-(4,4-dimethylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].Cl>C(Cl)(Cl)Cl>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
Glycine (7.5 g, 0.1 moles) is dissolved in 30 ml of aqueous sodium hydroxide solution (8 g, 0.2 moles) and cooled in ice and methacryloyl chloride (10.45 g, 0.1 moles), dissolved in 10 ml of chloroform, is added dropwise with stirring. After that, the reaction is allowed to continue for one hour at room temperature. The solution, cooled in ice, is acidified to a pH of 2 with 5N aqueous hydrochloric acid and exhaustively extracted with ethyl acetate. The organic solution is dried over sodium sulfate and evaporated under vacuum, 10 g (70%) of a crystalline product of N-methyacryloyl glycine with a melting point of 104° C. to 105° C. being obtained.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[S].[OH-].[Na+].[SH2:23]>>[CH2:10]([C:18]1[C:13]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:23][C:14]2([OH:19])[CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCc1ccccc1O
Reactant: S
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Product: CCCCCCCCCCCCC1=CC=CC2(O)SC12CCCCCCCCCCCC

Procedure:
A mixture of dodecyl phenol (1.0m., 262g.), sulphur (1.0m., 32g.) and caustic soda (8g.) was heated, with stirring, under nitrogen, at 160° C until the evolution of hydrogen sulphide ceased (42 hrs.). The caustic soda was neutralized with 10 ml. of phosphoric acid (SG = 1.75) and the mixture was then filtered. %S of Product = 5.85 (calc. = 5.8).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH3:10][N:11]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]1S(C)(=O)=O>CN(C)C=O>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][C:12]1[N:11]([CH3:10])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=1
Reactant: Cn1ccnc1S
Reactant: Cn1c([N+](=O)[O-])cnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ncc([N+](=O)[O-])n1C

Procedure:
A solution of 11.4 g of 2-mercapto-1-methyl-imidazole in 60 ml of dimethylformamide is added dropwise over the course of 15 minutes to a suspension of 4.8 g of 50% strength sodium hydride in 100 ml of dimethylformamide at 20° to 30° C, whilst stirring. The resulting solution is then added dropwise over the course of 30 minutes to a solution of 20.5 g of 1-methyl-2-methylsulphonyl-5-nitro-imidazole in 80 ml of dimethylformamide at 20° to 30° C whilst stirring. Thereafter the reaction mixture is stirred for a further hour at 100° C and is evaporated. The evaporation residue is extracted by shaking with 200 ml of methylene chloride and 200 ml of water and the methylene chloride extract is separated off, washed with 50 ml of water, dried over anhydrous magnesium sulphate and evaporated. After two recrystallisations from ethyl acetate the evaporation residue yields pure 1-methyl-2-[(1-methyl-5-nitro-2-imidazolyl)mercapto]-imidazole of melting point 123°-124° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[C:29]([O:33][C:34]([NH:36][C@H:37]([C:42](O)=[O:43])[CH2:38][CH2:39][S:40][CH3:41])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][CH:37]([CH2:38][CH2:39][S:40][CH3:41])[C:42](=[O:43])[S:18][CH2:17][C:16](=[O:19])[C@:15]1([OH:25])[C@:20]2([CH3:24])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:22]([OH:23])[CH2:21]2)[C@:3]2([CH3:28])[C:8](=[CH:7][C:6](=[O:27])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][C@@H:14]1[CH3:26])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCCC(NC(=O)OC(C)(C)C)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 79.8 %

Procedure:
The title compound (1.50 gm) was prepared from 1.20 gm of 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol and 2.20 gm of N-(t-butoxycarbonyl)-L-methionine in the same manner as in Synthetic Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([CH2:14][Br:15])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2cc(C)ccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(CBr)ccc2s1
Yield: 97.4 %

Procedure:
A mixture of 5-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (3.09 g.), N-bromosuccinimide (2.67 g.) and azobisisobutyronitrile (0.20 g.) in carbon tetrachloride (150 ml.) was heated under reflux for 5 hours. The mixture was then filtered and the filtrate was evaporated to give a solid which was crystallized from methanol to give 5-bromomethylbenzo[b]thiophene-2-carboxylic acid methyl ester (4.16 g.), m.p. 108°-110°.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([O:12][OH:13])([CH3:11])([CH3:10])[CH3:9]>>[CH3:6][C:5]([O:13][O:12][C:8]([CH3:11])([CH3:10])[CH3:9])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)(C)OO
Product: CC(=O)CC(C)(C)OOC(C)(C)C

Procedure:
Assay of the product by GLC indicated 76% product, 17% mesityl oxide, and 1% t-butyl hydroperoxide. The actual yield of product based on the t-butyl hydroperoxide consumed was 82%. Purification of product for GLC standard was accomplished by a double distillation under reduced pressure with a pot temperature of 40°±2° C. Fractions were collected and assayed. Micro analysis found: C, 64.10%; H, 11.10%; O, 24,96%. Calculated: C, 63.79; H, 10.71; O, 25.49; SN-7-249-95. cuts 5, 6, and 7 nD25 1.4170, cuts 1, 2, 3, 4 nD25 1.4167, 1.4167, 1.4167, 1.4169 respectively. Reference IR spectrum R-IR#6.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC(N(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(CCc2nc(-c3ccc(Br)cc3)oc2C)C1

Procedure:
Stir (1-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester (see Intermediate 10) with a 1:1 solution of trifluoroacetic acid and dichloromethane (0.30M) for 30 minutes at room temperature. After this time, quench the reaction with 1N sodium hydroxide and extract with dichloromethane. Extract from the organic layer with 1N hydrochloric acid. Basify the aqueous layer with 1N sodium hydroxide and extract with dichloromethane. Dry the organics with sodium sulfate, decant and concentrate in vacuo to yield the pure title compound, MS (m/e) (79Br/81Br): 364.1/366.0 (M+1)
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([OH:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[N:30][C:31]1[C:36]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:40]([CH3:42])[CH3:41])([CH3:18])[CH3:17]>O1CCCC1>[CH:40]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH:30][C:29]([O:13][N:8]1[C:9]([CH3:12])([CH3:11])[CH2:10][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1([CH3:15])[CH3:14])=[N:28][C:20]1[C:19]([CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:27])[CH3:26])([CH3:42])[CH3:41]
Reactant: CC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=Nc1c(C(C)C)cccc1C(C)C
Solvent: C1CCOC1
Product: CC(=O)OC1CC(C)(C)N(OC(=Nc2c(C(C)C)cccc2C(C)C)Nc2c(C(C)C)cccc2C(C)C)C(C)(C)C1
Temperature: 52 °C

Procedure:
To a solution of 4-acetoxy-1-hydroxy-2,2,6,6-tetramethylpiperidine (2.63 g, 12.2 mmol, [prepared as described in Example 1] in tetrahydrofuran (10 ml) is added bis(2,6-diisopropylphenyl)carbodiimide (4.52 g, 12.5 mmol) and the solution is heated to 52° C. under argon for 20 hours. The reaction mixture is evaporated and the residue chromatographed on silica gel with hexane-ethylacetate (5:1). The pure fractions are recrystallized from hexane to afford 1.87 g of the compound 10 as colorless crystals, mp. 144-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH:19]1[CH:24]=[C:23]([F:25])[C:22](F)=[CH:21][CH:20]=1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CCOCC.CS(C)=O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=3[F:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Reactant: Fc1ccccc1F
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN1CCC2(CC1)CN(c1ccccc1F)c1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6.3 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 1.5 g of sodium hydride, 10 g of O-difluorobenzene and 50 ml of dimethylsulfoxide is stirred at 60° C. under nitrogen for 30 minutes. Thereafter, the mixture is permitted to cool before adding ice-water. The biphasic mixture is extracted thrice with ether. The combined ether extracts are extracted with a large excess of dilute hydrochloric acid. The acidic extract is basified with concentrated ammonium hydroxide effecting a heavy oil. The oil is purified by passing through an alumina column, ether eluant, to provide a yellowish oil. The oil, in ether, is converted to its maleic acid salt which is recrystallized from an acetone-ether mixture providing off-white crystals, mp 166°-168° C. of 6-chloro-1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: C([O:4][C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[C:7]([CH3:17])[C:6]=1[CH3:18])(=O)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O1CCOCC1>[CH3:17][C:7]1[C:6]([CH3:18])=[C:5]([OH:4])[C:15]([CH3:16])=[CH:14][C:8]=1[O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:30]1[CH2:29][CH2:28][N:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:32][CH2:31]1
Reactant: CC(=O)Oc1c(C)cc(OCC2CO2)c(C)c1C
Reactant: COc1ccccc1N1CCNCC1
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC(O)COc2cc(C)c(O)c(C)c2C)CC1
Yield: 33.2 %

Procedure:
Using 3.88 g of 1-(4-acetoxy-2,3,5-trimethylphenoxy)-2,3-epoxypropane, 3.58 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup were carried out as in Examples 1-A and 4. After hydrolysis and workup, the residue obtained was recrystallized from benzene-hexane to give 2.06 g of white crystals, m.p. 163-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH2:13]([N:16]=[C:17]=[S:18])[CH2:14][CH3:15]>C(#N)C>[CH2:13]([NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1)[CH2:14][CH3:15]
Reactant: N#CCCCCn1ccc(N)n1
Reactant: CCCN=C=S
Solvent: CC#N
Product: CCCNC(=S)Nc1ccn(CCCCC#N)n1

Procedure:
A solution of 5-(3-aminopyrazol-1-yl)valeronitrile (1.0 g.) in acetonitrile (10 ml.) was treated with n-propylisothiocyanate (0.74 g.) and the solution heated under reflux on the steam bath for 6 hours. Evaporation of the solvent gave a brown gum which on trituration with ether/EtOH gave 5-(3-[3-propylthioureido]pyrazol-1-yl)valeronitrile as a white solid (1.01 g.).
Reaction SMILES: [CH:1]1([CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[C:19]([N:27]=C=O)(=[O:26])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:19]([NH2:27])=[O:26])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Temperature: 50 °C
Yield: 9.7 %

Procedure:
The crude 4-(2-cyclopropyl-2-phenyl-ethyl)-pyridin-2-ylamine (70 mg) is dissolved in methylene chloride (2 mL). Then benzoyl isocynate (86 mg, 0.59 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (2 mL) and potassium carbonate (61 mg, 0.44 mmol). The resulting mixture is heated at 85° C. for 45 min. Then solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×40 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 8 mg of the titled product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]([C:18](OCC)=[O:19])=[CH:16][N:15]=2)[S:11][CH:12]=1>CCOCC.C1COCC1>[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]([CH2:18][OH:19])=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[S:11][CH:12]=1
Reactant: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3ccccc3)c(CO)cn2)n1
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of 1M lithium aluminum hydride (70 mL, 70 mmol) in ether at 0° C. was added a solution of ethyl 6-(4-methylthiazol-2-ylamino)-4-phenoxynicotinate (14 mmol) in THF (50 mL). The reaction mixture was stirred for 1.5 hours, then slowly quenched with sodium sulfate decahydrate and stirred for 1 hour. The reaction mixture was filtered, the solids were washed with THF and the organic layer was concentrated. Water and ethyl acetate were added to the residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated to 50 mL of ethyl acetate, and filtered. The residue was purified using silica gel column chromatography with 30% ethyl acetate in hexanes as eluent to afford the desired product (3.0 g, 66% yield) as light yellow solid. 1H NMR (DMSO) δ 10.83 (s, 1H), 8.20 (s, 1H), 7.50 (m, 2H), 7.30 (m, 1H), 7.17 (m, 2H), 6.49 (d, 1H), 6.35 (s, 1H), 5.07 (t, 1H), 4.55 (d, 2H), 2.17 (d, 3H); Mass spectrum (esi) m/z=314 (100)(M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.Br[CH2:38][CH:39]1[CH2:43][CH2:42][O:41][CH2:40]1>CN(C)C=O>[F:35][C:33]([F:36])([F:34])[C:29]1[CH:28]=[C:27]([N:9]2[C:10]3[CH2:11][CH2:12][CH2:13][C:14](=[O:26])[C:15]=3[CH:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)[N:17]([CH2:38][CH:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[C:8]2=[O:7])[CH:32]=[CH:31][CH:30]=1
Reactant: BrCC1CCOC1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (67 mg, 0.486 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethylformamide (3 mL). 3-(Bromomethyl)tetrahydrofuran (60 mg, 0.365 mmol) is added, and the mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 12 mg; ESI mass spectrum [M+H]+=496; Retention time HPLC: 0.91 min (Z011_S03).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](OC)=[O:25])=[CH:18][CH:17]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[OH:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:28])=[CH:17][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(COc1ccc(CCCO)cc1)NCC(O)c1cccc(Cl)c1
Yield: 53.8 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 4.3 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.5 g of methyl 3-[4-(2-oxopropoxy)phenyl]propionate (prepared as described in Preparation 5), 150 ml of benzene, 150 ml of absolute methanol and 6.12 g of sodium borohydride were used. A crude product was obtained, and this was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 2.9 g of the title compound having an Rf=0.40 (thin layer chromatography over silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).