Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH2:25][CH2:26]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[O:22][CH3:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccccc1CCBr
Product: COc1ccccc1CCN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 52 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 6) and 2-methoxyphenethyl bromide. Yield: 52%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 4.03 (s, 2H), 5.17 (s, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.16-7.21 (m, 2H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 410.2. Found 410.1. Melting point: 97-98° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[O:13]1CCOCC1>Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:13])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccc(Br)cc2n1
Reactant: C1COCCO1
Agent: Cl
Product: O=c1ccc2ccc(Br)cc2[nH]1

Procedure:
7-Bromo-2-chloroquinoline was heated in 5M HCl (100 mL) and dioxane (10 mL) for 1 hour at reflux. The Reaction mixture was cooled, filtered and washed with water to give the title compound, 2.89 g, as a colorless solid, mp 295° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: O=C(O)Cc1ccsc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccsc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tIc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:33]1([CH2:39][CH2:40]O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[C:3]([O:13][CH2:40][CH2:39][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: OCCN1CCOCC1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1OCCN1CCOCC1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 30.6 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (34 mg, 0.13 mmol), triphenylphosphine (47 mg, 0.18 mmol), and 4-morpholineethanol (23 μL, 0.19 mmol) in tetrahydrofuran (0.38 mL, 4.6 mmol) at −10° C. was treated with diisopropyl azodicarboxylate (35 μL, 0.18 mmol) dropwise and stirred at −10° C. for 15 min and warmed to 20° C. for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate (5 mL), and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0%-60%) gave the desired product (15 mg, 31%). LCMS for C15H20BrClNO3 (M+H)+: m/z=376.0, 378.0. Found: 375.9, 378.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([Cl:27])[C:25]=1[Cl:26])[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([Cl:27])[C:25]=1[Cl:26])[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nc2cc(Cl)c(Cl)c(Cl)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 3,4,5-trichloroaniline (56 mg, 0.288 mmol) similar to Example 180 and was isolated as a white solid (30 mg, 37%). 1H NMR (CDCl3): 9.58 (d, J=1.5 Hz, 1H), 8.99 (ddd, J=8.4, 4.9, 1.5 Hz, 1H), 8.79 (dd, J=5.4, 1.5 Hz, 1H), 7.99 (s, 1H), 7.76 (dd, J=7.8, 5.1 Hz, 1H), 7.40 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][NH2:42])=[CH:40][C:35]=2[O:34][CH2:33]1>>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][NH:42][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]5[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=5)[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and C-benzo[1,3]dioxol-5-yl-methylamine, m.p. 154-155° C. MS [(+)ESI, m/z]: 590 [M+H]+ Anal. Calcd for C29H24BrN3O4S: C, 58.99; H, 4.10; N, 7.12. Found: C, 58.96; H, 4.26; N, 7.03.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([Cl:31])=[C:17]([NH:23]C(=O)OC(C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[NH2:23][C:17]1[CH:18]=[C:19]([CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:14][CH2:13]2)[C:16]=1[Cl:31])[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
(I13B): To a round bottom flask charged with tert-butyl (3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (I13A) (3.27 g, 7.02 mmol) in dichloromethane (35.1 ml) and cooled to 0° C. was added 2,6-lutidine (2.451 ml, 21.05 mmol). Trimethylsilyl trifluoromethanesulfonate (3.80 ml, 21.05 mmol) was added dropwise over 5 min. After 1 h, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate and dichloromethane. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the Isco system (120 g, 0-50% EtOAc/CH2Cl2). 3-amino-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzonitrile (I13B) (1.892 g) was isolated as a sticky yellow oil.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]#[N:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N)(=[S:28])C>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20](=[S:28])[NH2:21])=[CH:18][C:17]=1[C:24]#[N:25])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(C#N)c1
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1cc(C(N)=S)ccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A 4M HCl/1,4-dioxane solution was added to a DMF solution of 4-(benzyloxy)isophthalonitrile and thioacetamide, followed by stirring at 60° C. to obtain 4-(benzyloxy)-3-cyanobenzenecarbothioamide. AP: 291 (Na).
Reaction SMILES: N.[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1C[N:21]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15](=[O:17])[NH2:21])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Anhydrous ammonia gas was bubbled through a solution of (S)-(−)-1-(tert-butoxycarbonyl)-2-piperidine carboxylic acid (500 mg, 2.18 mmol) in DMF (50 ml) for 15 minutes. PyBop (1.25 g, 2.40 mmol) was added. After 5 hours, solvent was evaporated under reduced pressure. A solution of the resultant residue in ethyl acetate was washed with 5% citric acid (50 ml×3), 1 N NaOH (50 ml×3), dried with MgSO4, filtered, and concentrated to give 450 mg of (S)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a clear oil in 95% yield, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([S:20]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([F:41])=[CH:33][C:32]=2[C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[CH:25][C:24]=1[F:48])(=[O:22])=[O:21])[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:29][C:27]1[C:26]([O:30][C:31]2[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[C:34]([F:41])=[CH:33][C:32]=2[C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[CH:25][C:24]([F:48])=[C:23]([S:20]([NH:14][C:15]2[N:16]=[CH:17][S:18][CH:19]=2)(=[O:22])=[O:21])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cc(C(F)(F)F)c(F)cc2-c2ccnnc2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cc(C(F)(F)F)c(F)cc2-c2ccnnc2)cc1F
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (9 mL) was added to a solution of tert-butyl({5-chloro-2-fluoro-4-[4-fluoro-2-pyridazin-4-yl-5-(trifluoromethyl)phenoxy]phenyl}sulfonyl)1,3-thiazol-4-ylcarbamate (2.0 g, 3.1 mmol) in dichloromethane (20 mL). After 2 hours, the reaction mixture was concentrated in vacuo to afford the title compound as an amber foam (2.37 g).
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:10](=[O:25])[CH:9]([N:26]3C(=O)C4=CC=CC=C4C3=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>O1CCCC1>[NH2:26][CH:9]1[N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]1=[O:25]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(C2CCCCC2)c2ccccc2N1Cc1ccccn1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(C2CCCCC2)c2ccccc2N(Cc2ccccn2)C1=O
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A stirred solution of (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.22 g) in tetrahydrofuran (10 ml) was treated with a solution of hydrazine monohydrate (23 mg) in tetrahydrofuran (1 ml) at ambient temperature, and the mixture was stirred for 2 hours at the same temperature, then heated at reflux temperature for 1 hour. After cooling, the resultant precipitates were filtered off. The filtrate was concentrated in vacuo. The residue was taken up with 1N aqueous hydrohloric acid and washed with isopropyl ether. The aqueous layer was alkalined with sodium carbonate and extracted with chloroform. The extract was dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-3-amino-5-cyclohexyl-2,3-dihydro-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.12 g) as an yellow oil which was used in a following reaction step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CC1
Product: Cc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CC1
Yield: 28.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-methylphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.03 g, 30%) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCC(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 1-[4′-(trifluoromethyl)-4-biphenylyl]-1-pentanol (250 mg, 0.81 mmol) in dry DCM (15 mL) under nitrogen at 0° C. (ice/water bath) was added thionyl chloride (590 μL, 8.09 mmol) drop-wise. After stirring the mixture for 30 minutes at rt under nitrogen, the reaction was quenched by cautious addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3×30 mL). The organic extract was separated, washed with brine, dried (MgSO4) and the solvents removed under vacuum to afford the title compound as a yellow gum (251 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CC#N>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@H]1CO1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCC[C@H](O)CNc1ccc2c(c1)NC(=O)CS2
Temperature: 60 °C
Yield: 16 %

Procedure:
A mixture of (S)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (28.3 g, prepared according to Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]thiazin-3-one (23.6 g) in MeCN (390 mL) was treated with LiClO4 (41.8 g) and heated at 60° C. for 4 h. The volatiles were removed under reduced pressure and the residue partitioned between EA and brine. The org. phase was dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 1:1, EA) to give the desired intermediate as a yellowish foam (8.4 g; 16% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36]C(=O)C)[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:41][S:42](N[C@H](CC1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)(=[O:44])=[O:43]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 90 %

Procedure:
Using the procedure described in example 97f 0.140 g of 1-(2-(R)-methanesulfonylamino-3-phenyl-propionyl)-pyrrolidin-2-(S)-carboxylic acid was converted into 0.180 g (90%) of the title compound. (+)-APCI-MS: 496 (MH+).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CCOC(C)=O>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1
Reactant: C[O-]
Reactant: CC(C)CCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nc2c(N)nc(OCCC(C)C)nc2n1C1CCCCO1

Procedure:
To a solution of 8-bromo-2-[(3-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (314 mg) was added sodium methoxide solution (0.460 mL, 30% wt. MeOH) and the mixture was stirred at reflux for 4 h. The reaction was allowed to cool and was concentrated in vacuo to give an orange residue. The residue was taken up in EtOAc (20 mL) and was extracted with saturated ammonium chloride solution (20 mL), followed by water (20 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a light orange solid (210 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH3:9])[CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:14][C:15]1[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=1.O>CO>[CH3:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:14][C:15]1[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=1)[NH2:1]
Reactant: Cc1cc(N)ccc1S
Reactant: Cn1ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(N)ccc1SCc1nccn1C
Yield: 90.3 %

Procedure:
To a solution of 4-amino-2-methylthiophenol (500 mg) in methanol (10 ml) was added 1N aqueous solution of sodium hydroxide (12 ml), and a solution of 2-chloromethyl-1-methylimidazole hydrochloride (660 mg) in methanol (10 ml) was added at 0° C. Water was added to the mixture, and the mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate, to give 3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]aniline (757 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)c1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-pyridine (example E.19) (0.45 g, 1.0 mmol) and commercially available 3-pyridineboronic acid (0.32 g, 2.6 mmol) according to the general procedure VI. Obtained as a white solid (0.011 g, 3%). MS (ISP) 401.2 [(M+H)+] and 403 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Temperature: -18 °C
Yield: 38 %

Procedure:
1.64 g of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 3 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 42 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to approx. -18° C. and filtered. After the filter residue has been dried, 0.74 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate is obtained (38% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([OH:12])=[C:6]2[C:13]1[CH:24]=[CH:23][C:16]([C:17](N(OC)C)=[O:18])=[CH:15][N:14]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(OCC)(=O)C>[CH:17]([C:16]1[CH:23]=[CH:24][C:13]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][C:7]=2[OH:12])=[N:14][CH:15]=1)=[O:18]
Reactant: CON(C)C(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(C=O)cn3)c2c1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To an icecold suspension of 50 mg (0.16 mmol) of 6-(5-cyano-2-hydroxy-1H-indol-3-yl)-N-methoxy-N-methylnicotin-amide from example 1.2 in THF (4 mL) were added 19.4 mg (0.51 mmol) of LiAlH4 as a solid in small portions. The resulting mixture was stirred at that temperature for further 30 min. After diluting with ethyl acetate the reaction was quenched by adding 4.2 mL of a 0.35 M solution of KHSO4. The resulting solution was stirred for further 60 min, the phases were separated, and the precipitate in the organic layer was collected by filtration, washed with water and ethyl acetate, and dried in a vacuum oven yielding a red solid. Amount 28 mg. Yield 68%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([NH:33]C(=O)OCC3C=CC=CC=3)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:45])(=[O:44])[N:20]=1>CO.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:44])(=[O:45])[N:20]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A solution of Example 85 (56 mg, 0.086 mmol) in 7 mL of methanol was treated with 10% palladium on carbon (28 mg, 50 wt %) and placed under an atmosphere of hydrogen. The mixture was stirred at room temp for 5 h, filited through a 0.45 □M syringe filter, and concentrated in vacuo to afford the desired product (35 mg, 79% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.56 m, 2 H) 0.67 m, 6 H) 0.87 m, 2 H) 1.96 (m, J=11.40, 11.40 Hz, 2 H) 2.16 m, 2 H) 7.37 (s, 2 H) 7.59 m, 6 H) 8.15 (d, J=7.72 Hz, 1 H) 9.99 (s, 1 H) 13.94 (s, 1H); (ESI+) m/z 519 (M+H)+ (ESI+) m/z 536 (M+NH4)+ (ESI+) m/z 541 (M+Na)+ (ESI+) m/z 1054 (2M+NH4)+ (ESI−) m/z 517 (M−H)− (ESI−) m/z 1035 (2M-H)−.