Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1>C(O)=O>[NH:22]1[CH2:23][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][S:10]([C:7]3[S:6][C:5]4[CH:31]=[CH:32][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH3:9])(=[O:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH2:21]1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C3CN(C(=O)OC(C)(C)C)C3)c2)sc2ccc(Cl)cc12
Solvent: O=CO
Product: Cc1c(S(=O)(=O)Nc2cccc(C3CNC3)c2)sc2ccc(Cl)cc12
Yield: 102.7 %

Procedure:
tert-Butyl 3-(3-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (140 mg, 0.28 mmol) was stirred in formic acid (3 ml) at 0° C. for 3 h. The solution was concentrated, dissolved in water, concentrated HCl added and the solution concentrated by lyophylisation to give the title compound (113 mg, 93%) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([Sn](C)(C)C)=[CH:29][N:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]2[CH:29]=[N:28][C:27]([O:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:32][CH:31]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: C[Sn](C)(C)c1ccc(OCc2ccccc2)nc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1[N+](=O)[O-]
Yield: 103.9 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (728 mg, 2.0 mmol) and 2-(phenylmethoxy)-5-(trimethylstannyl)-pyridine (766 mg, 2.2 mmol) [CAS-No. [188881-22-3], WO 9709311] according to the general procedure E. Obtained as a yellow solid (876 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:39][CH:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43]>ClCCl>[CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][N:28]([C:42](=[O:43])[CH2:41][CH:40]([CH3:45])[CH3:39])[CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)CC(=O)Cl
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1CCC(c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of (R/S) tert-butyl methyl(2-(methyl((3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (200 mg, 0.46 mmol, 1.00 equiv) and triethylamine (1.14 g, 11.26 mmol, 24.52 equiv) in dichloromethane (15 mL) was added 3-methylbutanoyl chloride (67 mg, 0.56 mmol, 1.21 equiv). The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 2 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 250 mg of crude (R/S) tert-butyl methyl(2-(methyl((3-(1-(3-methylbutanoyl)piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate as a yellow solid. LCMS (method D, ESI): RT=1.22 min, m/z=520.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([C:22]1[C:23](=[O:33])[N:24]([CH3:32])[C:25](=[O:31])[N:26]([CH3:30])[C:27]=1[CH2:28]Br)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:30][N:26]1[C:27]2=[CH:28][N:1]([C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=3[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:22]2[C:23](=[O:33])[N:24]([CH3:32])[C:25]1=[O:31]
Reactant: CCOC(=O)c1ccc(O)c(N)c1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: CCOC(=O)c1ccc(O)c(-n2cc3c(c2-c2ccccc2)c(=O)n(C)c(=O)n3C)c1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
In a 100 mL round bottom flask ethyl 3-amino-4-hydroxybezoate (1.10 g, 6.07 mmol) and 4a (1.00 g, 2.98 mmol) were refluxed in ethanol (50 mL). After 2 h, the condenser was rearranged for distillation and ethanol (25 mL) was distilled off. The resulting solution was slowly poured into a vigorously stirred solution of ice cold water (200 mL) and citric acid (50 mg) giving a pink solid precipitate. The mixture was stirred for 10 min and then the solid was collected by filtration and rinsed with cold water to give 5h (1.23 g, 98.5%) after drying. The product was recrystallized from ethanol to give pale pink needles; m.p. 129.2-130° C. 1H NMR (600 MHz, CD2Cl2) δ 8.58 (s, 1H), 7.89 (dd, J=2.1, 8.7, 1H), 7.67 (d, J=2.1, 1H), 7.36-7.29 (m, 2H), 7.28-7.18 (m, 3H), 6.97 (d, J=8.7, 1H), 4.25 (q, J=7.1, 2H), 3.27 (s, 3H), 3.17 (s, 3H), 1.30 (t, J=7.1, 3H). 13C NMR (151 MHz, CD2Cl2) δ 165.40, 159.72, 156.82, 151.91, 136.06, 132.09, 130.86, 130.65, 129.49, 128.99, 128.83, 127.84, 125.70, 122.92, 117.65, 104.70, 103.11, 61.23, 32.02, 28.08, 14.24. MS (ES+) (m/z): [M+1]+ calculated for C23H22N3O5, 420.16. found 420.13.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=2)=[O:13])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)N2CC(Oc3ccccc3C(C)(C)C)C2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 4-{[3-(2-tert-butylphenoxy)azetidin-1-yl]carbonyl}phenol (552 mg, 1.7 mmol) obtained in Example 139 in DMF (20 mL) were added potassium carbonate (1.04 g, 7.5 mmol) and methyl bromoacetate (352 mg, 2.3 mmol), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 85:15-40:60) to give the title compound (578 mg, 69%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: N#CC1(S(=O)(=O)c2ccccc2Br)CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: N#CC1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)cyclopentanecarbonitrile. MS (ESI): mass calcd. for C22H19FN4O2S, 422.12; m/z found, 423.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.21 (dd, J=8.0, 1.0, 1H), 8.03 (d, J=1.4, 1H), 7.92 (m, 1H), 7.88-7.80 (m, 2H), 7.53 (d, J=7.6, 1H), 7.35 (dd, J=12.3, 1.5, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.74 (s, 2H), 2.21-2.04 (m, 4H), 1.71-1.67 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([CH2:11][NH:19][CH2:20][CH2:21][OH:22])=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNCCO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a suspension of 2-(benzyloxy)-4,6-dimethylnicotinaldehyde (Cpd JJ, 6.4 g, 27 mmol) in methanol (100 mL) was added 2-aminoethanol (8.34 mL, 133 mmol). The reaction mixture was stirred at room temperature for 1 hour then cooled to 0° C. Sodium cyanoborohydride (4.9 g, 66 mmol) was added in one portion and the reaction was slowly warmed to room temperature and stirred overnight. The methanol was removed under vacuum then the residue was diluted with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate, concentrated under vacuum and purified by column chromatography (EtOAc) to give 2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)-ethanol (Cpd KK, 4.2 g, 55% yield) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].ClCCl>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2nccs2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nccs1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (1.0 g, 1.561 mmol) in 20% trifluoroacetic acid/dichloromethane (100 mL) was stirred at room temperature for 30 minutes. The solvent was removed in vacuo then the crude residue azeotroped twice with toluene to give (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone trifluoroacetate as an orange solid (0.584 g). LCMS (Method F, ES-API): RT 1.30 min, m+H=381.0; 1H NMR (400 MHz, CDCl3): δ 8.02 (1H, d, J=2.7 Hz), 7.78 (1H, d, J=2.7 Hz), 7.48 (1H, s), 7.46-7.41 (2H, m), 7.24-7.16 (2H, m), 6.57 (1H, s), 4.45 (1H, d, J=12.5 Hz), 3.86 (1H, d, J=16.2 Hz), 3.74-3.65 (2H, m), 3.34 (1H, d, J=13.2 Hz), 3.12 (1H, br t, J=10.6 Hz), 2.89 (1H, d, J=16.2 Hz), 2.82 (1H, d, J=13.1 Hz), 2.62 (1H, d, J=15.4 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Cl)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CCl)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide (EP 0 659 737) (17.0 g, 42.8 mmol) was dissolved in 200 mL of dimethylformamide and treated with dibenzylamine (22.0 g, 110 mmol). The mixture was stirred at room temperature overnight and then the solvent was removed. The residue was purified by silica gel chromatography using 20-50% ethyl acetate/hexanes as elute to give the title compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.94 (s, 3H), 3.77 (s, 2H), 3.82 (s, 2H), 5.16 (s, 2H), 6.75 (brs, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.20-7.50 (m, 15H), 7.67 (dd, J=8.7, 2.1Hz, 1H), 8.10 (d, J=2.1 Hz, 1H); MS (ES) m/z: 515.2 (M++H); HRMS Calcd. for C30H30N2O4S(M+): 514.1926. Found: 514.1927.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(N)c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
4-Amino 3-nitro-benzonitrile (5.0 g, 0.03 moles) was dissolved in ethyl acetate then treated with 2.5 g of 10% Pd/C. The reaction mixture was flushed with hydrogen and allowed to stir overnight at 23° C. The reaction was not quite complete so 0.5 g more 10% Pd/C was added. After 2 hours the reaction was complete. The solution was filtered through celite, concentrated and used without further purification (4.67 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCC3
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a solution of methyl [2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl]pentanoate (0.081 g; 0.199 mmol) in methanol (4 mL) and ethanol (2 mL) was added a 5% sodium hydroxide solution (5.3 mL; 6.625 mmol). The reaction mixture was heated under reflux for 4.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.038 g (50%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2].[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].O>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][N:10]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2]
Reactant: CCOc1ncnc2[nH]cc(I)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
To 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (12, 2.70 g, 9.34 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (411.0 mg, 10.27 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then triisopropylsilyl chloride (3, 2.177 mL, 10.27 mmol) is added. The reaction is stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 5-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (13, 3.90 g).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.029 g, 27%). MP: 114-121° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.15 (s, 1H), 8.52 (d, 1H, J=8.3 Hz), 8.06-8.04 (m, 2H), 7.85 (s, 1H), 7.82-7.80 (m, 1H), 7.46 (s, 1H), 7.40-7.32 (m, 2H), 7.19 (t, 1H, J=7.7 Hz), 6.63 (s, 1H), 6.52-6.50 (m, 1H), 3.86 (s, 3H), 2.90-2.73 (m, 10H), 1.69 (t, 3H). MS: 540.43 (H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[C:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=[CH:5]2.[O:27]1[CH2:29][CH:28]1[CH2:30][OH:31].C(N(CC)CC)C>CCO>[OH:27][CH:28]([CH2:30][OH:31])[CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[C:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:6]=[CH:5]2
Reactant: OCC1CO1
Reactant: O=C(NCCC#Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCC#Cc1ccc2cc(OCC(O)CO)ccc2c1)OCc1ccccc1
Yield: 51.1 %

Procedure:
A solution of 4-(6-hydroxynaphthalen-2-yl)but-3-ynylcarbamate (30, 390 mg, 1.1 mmole), oxiran-2-ylmethanol (21, 0.1 mL, 1.4 mmole), and triethylamine (0.01 mL, 0.06 mmole) in absolute EtOH (8.8 mL) was subjected to microwave irradiation at 130° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford carbamate 31 (236 mg, 42%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.80 (s, 1H), 7.68 (dd, J=8.7, 3.9 Hz, 2H), 7.38-7.16 (m, 8H), 5.10 (s, 2H), 4.18 (dd, J=9.6, 4.2 Hz, 1H), 4.11-4.01 (m, 2H), 3.76-3.67 (m, 2H), 3.39-3.31 (m, 4H), 2.63 (t, J=6.9 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.FC(F)(F)C([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][C:30]1([CH3:33])[CH2:32][O:31]1)=O.[OH-].[NH4+]>CCO>[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][C:30]([OH:31])([CH3:33])[CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1
Reactant: CC1(COc2ccccc2NC(=O)C(F)(F)F)CO1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(COc1ccccc1N)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 5 h
Yield: 76.9 %

Procedure:
A solution of 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (1.10 g, 5.05 mmol), 2,2,2-trifluoro-N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}acetamide (1.39 g, 5.05 mmol) in EtOH (95%, 20 ml,) was stirred for 2 h at 78° C. Ammonium hydroxide (25%, 7.5 ml) was added to the reaction mixture and heating was continued for additional 5 h. After standing over night at room temperature the reaction mixture was concentrated and the residue was purified on silica (dichloromethane-methanol, 12:1, containing 1% of NH4OH (25%)) to give the subtitle compound (1.54 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:9]1.CI.[C:33](=O)([O-])[O-].[K+].[K+].CC(C)=O>>[F:1][C:2]1[CH:3]=[C:4]([N:26]([CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([OH:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)[CH2:9]1
Reactant: CS(=O)(=O)Nc1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide (20 mg, 0.00006 mol, example 312), methyl iodide (4.1 μL, 0.000066 mol), and potassium carbonate (10 mg, in excess) in acetone (2 mL, 0.03 mol) was stirred at rt for 2 h and then heated to 40° C. for 2 h. The reaction mixture was allowed to cool to rt and was purified by prep-HPLC to afford the desired product. LC-MS: 454.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:28]([NH:27][C:19]1[C:18]([CH:15]([CH3:16])[CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:24]([CH3:26])[CH3:25])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)c1ccccc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzylphenylamine (1.3 g) and 2,6-diisopropylphenyl isocyanate (1.7 mL) as starting materials, N-benzyl-N′-(2,6-diisopropylphenyl)-N-phenylurea (1.8 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][NH2:23]>C(O)(C)C>[CH3:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CN
Reactant: O=C(c1ccccn1)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Solvent: CC(C)O
Product: CNc1ccc(C2(C(=O)c3ccccn3)CC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 231d from [1-(4-chloro-3-nitro-phenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone and methylamine in isopropanol.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:21]=[CH:20]2.Cl>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:29])=[O:28])[CH:21]=[CH:20]2
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Glycine ethyl ester hydrochloride (9.88 g) was suspended in methylene chloride (500 ml), and triethylamine (20.2 ml) and then 6-chloronaphthalene-2-sulfonyl chloride (17.6 g) were added to the suspension under cooling with ice. After stirring at room temperature for 1 hour and adjusting the mixture to pH 2 by addition of 1N hydrochloric acid, the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After washing the resulting crystals in n-hexane, the crystals were collected by filtration and air-dried to obtain the title compound (22.4 g).