Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=[N:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:2]1.[Si]([C:17]#[N:18])(C)(C)C>C(Cl)Cl>[C:17]([C:3]1([NH:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:4][CH2:5][O:1][CH2:2]1)#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)S(=O)N=C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)CCOC1
Reaction time: 12 h
Yield: 47 %

Procedure:
To a solution of Intermediate 334A (300 mg, 1.585 mmol) in DCM (10 mL) at RT was added TMSCN (198 μL, 1.477 mmol) dropwise, followed by Ti(OEt)4 (318 μL, 1.426 mmol). The resulting solution was stirred for 12 h. The reaction was quenched by pouring it into a vigorously stirred saturated aq. solution of NaHCO3 (20 mL). The precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude compound was triturated with diethyl ether to afford Intermediate 334B (150 mg, 44% yield) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.48-6.36 (m, 1H), 4.05 (d, J=9.0 Hz, 1H), 3.87 (d, J=8.5 Hz, 3H), 2.49-2.33 (m, 2H), 1.21-1.10 (m, 9H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH2:21][CH2:22][NH2:23])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH2:24]([CH2:28][C:29](=O)[CH3:30])[C:25]([CH3:27])=O.[Al]>CN(C)P(=O)(N(C)C)N(C)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH2:21][CH2:22][N:23]2[C:29]([CH3:30])=[CH:28][CH:24]=[C:25]2[CH3:27])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: NCCc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CC(=O)CCC(C)=O
Agent: [Al]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc(C)n1CCc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 3-sulphamoyl-4-phenoxy-5-[β-aminoethyl]-benzoic acid (5.0 g=1.35 mmols; see Example 3 for the preparation), acetonylacetone (1.85 g, approximately 16.2 mmols) and hexamethylphosphoric acid triamide (Hexametapol; 25 ml) is warmed at 100° for 30 minutes under N2 in an apparatus which has been protected against incident light by covering it with aluminium foil, and the reaction solution is worked up as follows, with strict exclusion of light throughout: pouring into ice-water (50 ml) and extracting with ethyl acetate, washing the extract with water, drying and filtering and evaporating the filtrate. The crude product is recrystallised from chloroform/cyclohexane with the addition of active charcoal and gives pale orange-coloured, light-sensitive crystals, melting point>210° (decomposition).
Reaction SMILES: [C:1](Cl)([Cl:3])=[S:2].[C:5]1([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC>C1COCC1>[Cl:3][C:1]([S:16][C:15]1[N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:12]=[N:13][N:14]=1)=[S:2]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C(Cl)Sc1nnnn1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a solution of thiophosgene (1.29 g, 0.0112 mol) in THF (40 ml) at 5° C. was added a solution of 1-phenyl-1H-tetrazole-5-thiol (2.0 g, 0.0112 mol) and Et3N (1.94 ml, 0.0134 mol) in THF (30 ml). The mixture was stirred at 5° C. for 30 min and then at r.t. for 1 hr. 20 min. The precipitate was filtered and washed with THF. The filtrate was evaporated in vacuo. To the obtained residue was added ether and the insoluble material was filtered off. The filtrate was evaporated in vacuo to give a solid which was recrystallized from CHCl3 --hexane. 0.91 g of the compound was obtained. 27.6% yield. IR (Nujol): 1725, 1585 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(-n2cccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(-n2cccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 1-(4-hydroxyphenyl)pyrrole (0.8 g), potassium carbonate (3.2 g) and 1-bromo-3-chloropropane (2.5 mL) in N,N-dimethylformamide (10 mL) affords 1.37 g of 1-[4-(3-chloropropoxy)phenyl]pyrrole as a brown solid used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[OH:19])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[O:19][S:36]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCn1ncc(C(=O)c2ccc(Cl)c3ncccc23)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(Cl)c3ncccc23)c1OS(=O)(=O)c1ccc(Cl)cc1

Procedure:
1.00 g of 4-[(8-chloroquinolin-5-yl)carbonyl]-1-ethyl-5-hydroxy-pyrazole, 0.70 g of triethylamine and 0.70 g of 4-chlorobenzenesulfonyl chloride in 15 ml of methylene chloride were stirred at room temperature for 12 hours. The reaction mixture was then poured into aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated and the residue was purified by chromatograpy over silica gel.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([S:30]([CH2:32][CH3:33])=[O:31])[C:24](C(F)(F)F)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[ClH:34]>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([S:30]([CH2:32][CH3:33])=[O:31])[C:24]([Cl:34])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)CC)cc3n2COCCOC)c1
Reactant: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)CC)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.191 g, 0.420 mmol) in ethanol (2 mL) was added 4M HCl in dioxane (2 mL). The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was collected and rinsed with diethyl ether to yield the titled compound (0.103 g, 67% yield). MS (ESI/CI): mass calcd. for C15H15ClN4O3S, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.02 (d, J=0.6 Hz, 1H), 8.40 (d, J=0.6 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.17 (dq, J=14.6, 7.3 Hz, 1H), 2.84 (dq, J=14.6, 7.4 Hz, 1H), 1.32 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19](O)C.CI>O>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11]([S:15][CH3:19])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1ccccc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Temperature: 60 °C

Procedure:
5-Benzyl-6-methylthiouracil (6.0 gms) and sodium hydroxide (1.06 gms) were dissolved in water (30 mls). The solution was cooled and ethanol (60 mls) and methyl iodide (3.67 gms) added with stirring. The mixture was heated at 60° C. for 1/2 hour, cooled and the resulting solid collected and water-washed. A second crop of solid was obtained by acidification of the filtrate to pH=4 with acetic acid. Recrystallisation from ethanol produced 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (5.33 gms) m.p.=220°-221.5° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[NH:36][CH:37]=[CH:38][C:31]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:36]1[C:32]2=[N:33][CH:34]=[CH:35][C:30]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=4)[C:13](=[O:27])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:28])[N:6]=3)[CH2:3][CH3:4])=[C:31]2[CH:38]=[CH:37]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (40 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 13A).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([I:16])C(=O)C1>>[F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[C:6]([I:16])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ncccc1F
Product: Nc1ncc(I)cc1F

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 200 mg (1.78 mmol) 3-fluoro-pyridin-2ylamine and 401 mg (1.78 mmol) NIS. Yield after precipitation from the reaction mixture: 380 mg (90%).
Reaction SMILES: C1(CN2CCN(C3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)=[CH:22][N:23]=4)=CC=3)CC2)CC1.BrC1N2N=CN=C2C(NC2C=C[C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]3)=[C:45]([C:58]([F:61])([F:60])[F:59])[CH:44]=2)=NC=1>>[CH:55]([N:52]1[CH2:53][CH2:54][N:49]([C:46]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:19]4[N:20]([N:29]=[CH:30][N:31]=4)[C:21]([C:24]4[CH:25]=[N:26][NH:27][CH:28]=4)=[CH:22][N:23]=3)=[CH:44][C:45]=2[C:58]([F:61])([F:60])[F:59])[CH2:50][CH2:51]1)([CH3:57])[CH3:56]
Reactant: c1nc2c(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)ncc(-c3cn[nH]c3)n2n1
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2C(F)(F)F)CC1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ncnc34)cc2C(F)(F)F)CC1

Procedure:
This compound may be prepared using methods as described for Compound 46, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-isopropylpiperazin-1-yl)-3-trifluoromethylphenyl]amine. LCMS: Rt=0.99 (95%), m/z (ESI) 472 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2ccccc12
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-methylindole (15.0 g, 114 mmole) in dry DMF (200 mL) was added NaH (60% dispersion in oil, 5.0 g, 125 mmole) in portions. Gas evolution was observed. The mixture was stirred for 30 min, then iodomethane (8 mL, 129 mmole) was added in one portion. The reaction became exothermic and was cooled in an ice bath. After 16 hr at RT, the reaction was concentrated under vacuum and the residue was taken up in ethyl acetate. The solution was washed with H2O then with brine, dried (MgSO4), and concentrated to dryness. Purification by short path distillation under vacuum (bp 88-92° C., 0.5 mmHg) gave the title compound (16.10 g, 97%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.9 Hz, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 7.13 (t, 1 H), 7.06 (s, 1 H), 7.00 (t, 1 H), 3.71 (s, 3 H), 2.24 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)=[CH:4][CH:3]=1.C1(P(Cl)([Cl:30])=O)C=CC=CC=1>>[Cl:30][C:12]1[CH:11]=[CH:10][C:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: O=c1ccc(C(c2ccccc2)c2ccc(Cl)cc2)c[nH]1
Product: Clc1ccc(C(c2ccccc2)c2ccc(Cl)nc2)cc1
Reaction time: 8 h

Procedure:
Combine 50 g. (0.174 mole) of the 5-substituted 2-pyridone from step A with 125 ml. of phenylphosphonic dichloride and heat at 210°-220° C. for about 7 hours with stirring. Allow to stand overnight and pour onto ice. Basify with ammonium hydroxide and extract with ethyl ether. Dry the ether solution and concentrate to a residue. Distill the residue and collect the fraction boiling at 205°-215° C. at 0.55 mm. (49 g.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)=[CH:24][C:25](=[O:26])[NH:14][C:5]=23)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: Cc1n[nH]c(N)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=O)[nH]c3c(-c4ccc(Cl)cc4)c(C)nn23)cc1
Yield: 48.2 %

Procedure:
3-Methyl-4-(4-chlorophenyl)-1H-pyrazol-5-amine (166 mg) and ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (266 mg) are stirred overnight at 95° C. in a pyridine (10 mL) solvent. After lowering reaction temperature to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and 141 mg of the target compound is obtained by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 11.40 (br, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.44 (m, 4H), 6.97 (d, J=8.7 Hz, 2H), 4.06 (br, 1H), 3.89 (s, 3H), 2.17 (s, 3H), 2.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 4-benzyloxy-3-nitro-benzoic acid (36 g, 132 mmol) in toluene (1000 mL) and dimethylformamide (3 mL) was treated with thionyl chloride (47 g, 28.7 mL, 395 mmol) and stirred at 90° C. for 18 hours. The volatiles were evaporated completely and the residue dried under high vacuum. 4-Benzyloxy-3-nitro-benzoyl chloride thus obtained (37.5 g, 97%) was used crude in the following reaction.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:15]1[CH:20]=[CH:19][N+:18]([CH3:21])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].CO.[BH4-].[Na+]>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: C[n+]1ccc(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodide was mixed with MeOH (400 ml) and CH2Cl2 (200 ml), then treated with NaBH4 (2.5 g) in portions. After stirring at RT for 2 h, the mixture was extracted with CH2Cl2 (300 mL×3). The CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, to provide the desired product.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:38]([O:37][C:35]([C:32]([CH3:34])([CH3:33])[CH2:31][CH:10]1[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]1([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30])[C:21]#[N:22])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)C(=O)OCc2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(=O)OCc1ccccc1
Yield: 86 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 103b (0.98 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white gum (0.94 g, 86%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12].[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([CH3:16])[CH3:15]>CC(O)C.C[O-].[Na+]>[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:3](=[O:13])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:11]1[SH:12])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: CC(C)c1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)c1ccccc1-n1c(S)nc2ccccc2c1=O
Yield: 54.9 %

Procedure:
2-Isothiocyanato-benzoic acid methyl ester (0.58 mL, 3.69 mmol) was added to a solution of 2-isopropyl aniline (500 mg, 3.69 mmol) and sodium methoxide (10 mg) in 2-propanol (10 mL) at room temperature and heated at reflux for 16 hr. The reaction mixture was concentrated to dryness under vacuum. The crude material was washed with dichloromethane (2×10 mL), 10% methanol in chloroform (2×10 mL) and dried under reduced pressure to afford 3-(2-isopropyl-phenyl)-2-mercapto-3H-quinazolin-4-one (600 mg, 55%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8](C)[CH3:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.CN>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(C)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: CN
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
6-chloro-2-methylamino-3-nitro-pyridine was prepared in accordance to the procedure described above for the preparation of 6-chloro-2-dimethylamino-3-nitro pyridine by using solution of methyl amine. The crude product was purified by flash chromatography, eluting with 90% hexane: 10% ethyl acetate to 16 (300 mg).
Reaction SMILES: [O:1]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)COc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)Oc1ccccc1
Reaction time: 4 h

Procedure:
Methyl phenoxyacetate (5.0 g, 30 mmol), N-bromosuccinimide (5.4 g, 30 mmol), a few crystals (0.2 to 0.5 g) of benzoyl peroxide, and 50 mL of carbon tetrachloride were placed in a 100 ml flask and heated at reflux with stirring for about 4 hr. The mixture was then allowed to cool, was filtered, and was concentrated by evaporation under reduced pressure to obtain 6.6 g (90 percent of theory) of the title compound as a red oil.
Reaction SMILES: [CH3:1][C:2]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42]Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC#N.CCN(C(C)C)C(C)C>[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccn2)nc2ccccc21

Procedure:
Using General Procedure A: Reaction of 2-[4-(1-methyl-1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione in dry CH3CN, N-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole, DIPEA and KI gave 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3) δ 1.18-1.33 (m, 2H), 1.39-1.54 (m, 2H), 1.52 (s, 6H), 1.71 (s, 9H), 2.65 (t, 2H, J=7.5 Hz), 3.43 (t, 2H, J=7.2 Hz), 4.27 (s, 2H), 7.04 (t, 1H, J=4.8 Hz), 7.19-7.31 (m, 3H), 7.55 (td, 1H, J=7.7, 1.7 Hz), 7.62-7.70 (m, 2H), 7.70-7.78 (m, 2H), 7.81 (dd, 1H, J=6.6, 1.6 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.47 (d, 1H, J=3.9 Hz). Deprotection with H2NNH2.H2O using General Procedure E gave a colorless oil. Conversion to the HBr salt gave COMPOUND 222 as a white solid. 1H NMR (D2O) δ 1.36-1.51 (m, 4H), 1.60 (s, 6H), 2.46-2.59 (m, 2H), 2.72-2.84 (m, 2H), 4.56 (s, 2H), 7.54-7.64 (m, 2H), 7.74-7.84 (m, 2H), 8.03 (t, 1H, J=6.6 Hz), 8.21 (d, 1H, J=8.4 Hz), 8.64 (t, 1H, J=7.8 Hz), 8.85 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 23.21, 24.88, 26.01, 39.43, 45.77, 53.70, 63.80, 114.23, 125.75, 126.73, 126.84, 131.03, 142.12, 148.73, 153.74, 160.26; ES-MS m/z 338 (M+H). Anal. Calcd. for C20H27N5.3.0HBr.1.4H2O.0.3C4H10O: C, 40.57; H, 5.75; N, 11.16; Br, 38.19. Found: C, 40.48; H, 5.67; N, 11.01; Br, 38.18.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(O)C>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][NH:21][CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN
Reactant: ClCCCC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCCNCCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 15.0 g. of 1,1-diphenyl-4-chlorobutane and 35 cc. of propylamine in 75 cc. of ethyl alcohol was heated in a sealed bomb at 100° C. for 16 hours. After cooling the reaction mixture to about 25° C., the solvent was removed under reduced pressure. The product was dissolved in 100 cc. of diethyl ether and washed with 5 N sodium hydroxide, and the product was extracted with 2 N hydrochloric acid. The aqueous acidic extracts were combined and the pH was adjusted to 11 by the addition of 5 N sodium hydroxide. The product was insoluble in the aqueous basic solution and was extracted therefrom into diethyl ether. The ethereal extracts were combined, washed with water and dried, and hydrogen chloride gas was added to the ethereal solution. The hydrochloride salt of 1,1-diphenyl-4-n-propylaminobutane crystallized and was collected by filtration. m.p. 94°-96° C.