Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:15])[CH:7]=1>O1CCCC1>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
Borane-dimethyl sulfide complex (2M in THF; 116 mL, 0.232 mol) is added slowly to a solution of 4-bromo-2-methylbenzoic acid (24.3 g, 0.113 mol) in anhydrous tetrahydrofuran (THF, 146 mL) at 3° C. After stirring cold for 10 min the cooling bath is removed and the reaction is allowed to warm slowly to ambient temperature. After 1 hour, the solution is cooled to 5° C., and water (100 mL) is added slowly. Ethyl acetate (100 mL) is added and the phases are separated. The organic layer is washed with saturated aqueous NaHCO3 solution (200 mL) and dried over Na2SO4. Filtration and concentration under reduced pressure gives a residue which is purified by filtration through a short pad of silica eluting with 15% ethyl acetate/iso-hexane to give the title compound (20.7 g, 91.2% yield). MS (m/z): 183/185 (M+1-18).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:18])[CH2:16]N.C(O)(=[O:21])C.N([O-])=O.[Na+]>O>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:18])[CH2:16][OH:21]
Reactant: CC(=O)O
Reactant: CC(CN)c1ccc2c(c1)Cc1ccccc1O2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
2.4 g. of 2-(2-xanthenyl)-propylamine (obtainable from 2-(2-xanthenyl)-propionamide with LiAlH4) is dissolved in 50 ml. of 15% aqueous acetic acid and mixed, under ice cooling, with a solution of 1 g. of NaNO2 in 5 ml. of water. The mixture is heated for 1 hour to 80°, worked up as usual, and chromatographic purification on silica gel yields 2-(2-xanthenyl)-propanol, m.p. 86°-89°.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>ClCCl>[CH:14]1([NH:17][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)NC2CC2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To 4-chlorosulfonylbenzoic acid (10.0 g, 45.3 mmol) in dichloromethane (350 mL) at 0° C. was added cyclopropanamine (15.5 g, 19 mL, 271.9 mmol). The reaction mixture was allowed to warm to room temperature over 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in water (150 mL) and acidified using hydrochloric acid. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(cyclopropylsulfamoyl)benzoic acid (10.0 g, 92%) as a white solid. ESI-MS m/z calc. 241.0. Found 242.5 (M+1)+; Retention time: 0.84 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 2.03-1.90 (m, 1H), 0.38-0.28 (m, 2H), 0.23-0.15 (m, 2H).
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([CH3:27])[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[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:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:27])=[CH:20][CH:21]=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#Cc1ccc(C)cc1
Product: Cc1ccc(C#Cc2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Yield: 89.7 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (728 mg, 2.0 mmol) and 4-tolylacetylene (349 mg, 3.0 mmol) according to the general procedure F. Obtained as a yellow solid (632 mg).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C>[N:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH2:8])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1
Reactant: c1ccc(CN(CCC2CCN(c3ccncc3)CC2)Cc2ccccc2)cc1
Solvent: CCO
Product: NCCC1CCN(c2ccncc2)CC1
Reaction time: 48 h
Yield: 94 %

Procedure:
N,N-Dibenzyl-2-(1-(pyridin-4-yl)piperidin-4-yl)ethanamine (1.4 g, 3.63 mmol, 1 eq) was dissolved in ethanol (80 ml) and degassed for 30 min with nitrogen. 20% Pd(OH)2 (800 mg) was added and hydrogenation was carried out for 48 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and washed with ethanol (200 ml), and the filtrate was reduced under reduced pressure. Yield: 94% (700 mg, 3.41 mmol).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43](C)=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([S:46][CH3:47])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=C([C@H]2OC(=O)N(CC3C(B4OC(C)(C)C(C)(C)O4)=CN=C(SC)N=3)[C@H]2C)C=C(C(F)(F)F)C=1>>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([S:46][CH3:47])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Product: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
INTERMEDIATE 45 was prepared similarly to INTERMEDIATE 43 by combining INTERMEDIATE 21 and INTERMEDIATE 34 to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 8.38 (s, 1H), 8.26 (d, 1H), 7.98 (s, 1H), 7.93 (d, 1H), 7.88 (s, 1H), 7.74 (s, 2H), 7.51 (d, 1H), 7.32 (d, 1H), 5.71 (d, 1H), 4.82 (d, 1H), 4.43 (br, 1H), 4.10 (m, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 2.62 (s, 3H), 2.38 (s, 3H), 0.75 (d, 3H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]2[N:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]=1>C(O)(=O)C>[N:5]1[CH:4]=[CH:3][N:7]2[C:6]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:9]1[N:17]=[CH:18][CH:19]=[CH:20][C:8]2=1
Reactant: COC(CNC1=Nc2cccnc2Nc2ccccc21)OC
Solvent: CC(=O)O
Product: c1ccc2c(c1)Nc1ncccc1-n1ccnc1-2
Temperature: 105 °C
Yield: 74 %

Procedure:
A mixture of N-(2,2-dimethoxyethyl)-11H-pyrido[2,3-b][1,4]benzodiazepin-6-amine (4.21 g, 14 mmol) and acetic acid (20 mL) was heated to 105° C. for 13 hours. After cooling to room temperature the solvent was removed under reduced pressure. The resulting crude product was diluted with acetone and filtered by suction to give a dark pink solid (74%). 1H NMR (DMSO-d6) 400 MHz δ: 8.53 (s, 1H), 8.15 (dd, J=4.6, 1.7 Hz, 1H), 7.85 (dd, J=7.7, 1.4 Hz, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.28 (td, J=8.0, 1.7 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.19 (dd, J=8.0, 1.2 Hz, 1H), 7.11 (dd, J=7.7, 4.6 Hz, 1H), 7.02 (td, J=7.5, 1.2 Hz, 1H); LC/MS [M+H]: 235.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>C(O)C>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 24 h

Procedure:
As experimental animals, overnight fasted SD rats (Japan SLC. Inc., male, 7-8 weeks of age, 205-272 g) were used. A Test compound was suspended in 0.5% sodium carboxymethylcellulose solution at the concentration of 2 mg/mL. When a homogenous suspension was not obtained in this condition, the test compound was dissolved in ethanol at the concentration of 100 mg/mL of its active form and then 2 mg/mL suspension was obtained by adding this solution to 49 times volumes of 0.5% sodium carboxymethylcellulose solution. Apart of this suspension was diluted with 0.5% sodium carboxymethylcellulose solution and then 0.6 and 0.2 mg/mL suspensions were prepared. After the body weights of rats were measured, the test suspension was orally administered at the dose of 5 mL/kg (1, 3 and 10 mg/kg). For control, just only 0.5% sodium carboxymethylcellulose solution was orally administered at the dose of 5 mL/kg. Immediately after this oral administration, 500 g/L sucrose solution was orally administered at the dose of 5 mL/kg (2.5 g/kg). The oral administration was performed with gastric tube for rat and 2.5 mL syringe. The head count in one group was 3. Collection of urine was performed in metabolic cage after the sucrose administration was finished. The sampling time for collection of urine was 24 hours after the sucrose administration. After collection of urine was finished, the urine volume was recorded and the urinary glucose concentration was measured. The glucose concentration was measured with a kit for laboratory test: Glucose B-Test WAKO (Wako Pure Chemical Industries, Ltd.). The amount of urinary glucose excretion in 24 hours per 200 g of body weight was calculated from urine volume, urinary glucose concentration and body weight. The results are shown in the following Table 4.
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C.N>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][CH2:10][CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: NCCOc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCOc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared by reacting 2-phenoxyethylamine hydrochloride (0.80 g, 4.6 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol) in dioxan (25 ml) in the presence of triethylamine (1.0 g, 9.6 mmol) followed by deprotection of the purified product using methanolic ammonia to provide the title nucleoside (0.75 g, 60%)(following flash chromatography) as an amorphous foam, 1H NMR (DMSO-d6)δ 3.52-3.59 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.82 (2H, q, --OH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, q, H-2'), 5.12 (1H, t, 5'-0H), 5.25, 5.54 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.92-7.02 (3H, m, Ar--H), 7.26-7.34 (2H, t, Ar--H), 8.46 (1H, m, H-8), 8.56 (1H, br, t, N--H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[NH:7][C:4]1[NH:3][C:2]([CH3:1])=[N:6][N:5]=1
Reactant: COC1CCCCC1=O
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC1CCCCC1Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and 2-methoxycyclohexanone (3.9 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.8 g, 51%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCC(CN3CCc4ccccc4C3)CC2)cc1

Procedure:
The title compound was prepared from 1,2,3,4-tetrahydroisoquinoline, 1-benzyl-piperidine-4-carbaldehyde (from Example 162, step A), diisopropylethylamine and sodium triacetoxyborohydride using a procedure analogous to that described in Example 1,, Step J.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:10][CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:2]([CH3:1])[C@@H:3]([CH2:10][CH3:11])[CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC[C@@H](CN1CCCC1)NC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@@H](CN1CCCC1)N(C)C(=O)c1ccc(Br)cc1
Yield: 61.4 %

Procedure:
To a solution of (S)—N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M5) (75 mg, 0.48 mmol) in DCM (1.5 mL) was NMM (0.058 mL, 0.53 mmol) and 4-bromobenzoyl chloride (137 mg, 0.62 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL), washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (100 mg, 62%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.92, 1.33-1.66, 1.66-1.97, 2.55, 2.94, 3.64, 4.70-4.83, 7.21-7.49, 7.49-7.76. Ratio major:minor:3:2. Total no of protons: 23.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1>>[CH2:18]([O:17][CH2:16][CH2:15][N:14]1[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=[C:10]1[CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:19]
Reactant: C1CNCCNC1
Reactant: CCOCCn1c(CCl)nc2ccccc21
Product: CCOCCn1c(CN2CCCNCC2)nc2ccccc21
Yield: 65.8 %

Procedure:
In the same manner as described in Example 1, homopiperazine (8.0 g) and 2-chloromethyl-1-(2-ethoxyethyl)benzimidazole (2.4 g) obtained in the same manner as described in Reference Example 3 are reacted to give 1-(2-ethoxyethyl)-2-(1-homopiperazinyl)methylbenzimidazole (2.0 g) as a pale yellow liquid. This liquid is treated with fumaric acid (1.15 g,), and the crude crystal thus obtained is recrystallized from a mixed solvent of ethyl acetate-ethanol to give 1-(2-ethoxyethyl)-2-(1-homopiperazinyl)methylbenzimidazole 3/2 fumarate (1.75 g) as colorless prisms, m.p. 151°-152° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22]
Reactant: CC(C)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: CC(C)CNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and isobutylamine employing methods similar to those described in Example 2 and was obtained as a white solid; 1H NMR (d6-DMSO) δ 10.82 (1H, br), 8.22 (1H, s), 7.35-7.22 (6H, m), 4.03 (2H, s), 3.11 (2H, br), 1.77 (1H, m), 0.92 (6H, d, J=6.5 Hz); HRMS calcd for C20H21N3O3+H+: 352.1661. Found: 352.1645.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]1([NH:23][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]4[S:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[O:16])[O:10][N:9]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: O=C(NCC1CC(c2ccc(Br)cc2)=NO1)c1ccc(Cl)s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C(NCC1CC(c2ccc(Nc3ccccc3)cc2)=NO1)c1ccc(Cl)s1

Procedure:
Aryl Bromide (Example 1, 100 mg, 0.25 mmol), aniline (27 uL, 0.30 mmol), Cs2CO3 (163 mg, 0.50 mmol) and Xantphos (43 mg, 0.075 mmol) were diluted with 4 mL of degassed THF. The resulting suspension was degassed for an additional 3 min then Pd2(dba)3 (23 mg, 0.25 mmol) was added giving a dark violet suspension which became dark yellow-orange within a few minutes. The mixture was then refluxed overnight, changing to cloudy orange as the aryl bromide was consumed. The next day the mixture was partitioned with water and ethyl acetate, separated, and the organic layer extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated and purified by preparative HPLC affording the desired product as a white powder. MS found for C21H18ClN3O2S as (M+H)+ 412.0, 414.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([S:17]([CH2:20]Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:20][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])([O-:3])=[O:2]
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1ccccc1

Procedure:
4-nitro-fluorobenzene and phenylsulfonylmethyl chloride were reacted in dimethylsulfoxide in the presence of potassium tert.-butylate to form 4-nitro-3-(phenylsulfonylmethyl)-fluorobenzene which was reacted with N-hydroxy-phthalimide to form 0-[4-nitro-3-(phenylsulfonylmethyl)-phenoxy]-phthalimide which was reacted to obtain 0-[4-nitro-3-phenylsulfonylmethyl)-phenyl]-hydroxylamine melting at 195°-196° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=3)=[O:34])[N:31]=2)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][C:29]1[S:28][C:27]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[N:31][C:30]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(NC(=O)Nc2nc(-c3ccncc3)sc2Br)n1
Temperature: 25 °C

Procedure:
NBS (686 mg, 3.85 mmol) and AIBN (158 mg, 0.96 mmol) were added to a heterogeneous solution of 1-((2-pyridin-4-yl)thiazol-4-yl)-3-(6-methylpyridin-2-yl)urea (600 mg, 1.93 mmol, Example 6) in CCl4 (25 mL) and the resulting mixture was heated at reflux for 2 h. After cooling to RT, a precipitate formed and was collected, rinsing with hexane to give a white solid. MS m/z: 392.0 (M+2H). Calc'd for C15H12BrN5OS-390.26.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]4[C@H:33]([CH2:34][O:35][CH3:36])[O:32]C5(CCCCC5)[O:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[ClH:42]>CCO>[ClH:42].[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]([OH:30])[C@@H:33]([OH:32])[CH2:34][O:35][CH3:36])[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC3(CCCCC3)O[C@H]2COC)ns1
Agent: Cl
Solvent: CCO
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)[C@@H](O)COC)ns1
Temperature: 50 °C
Yield: 64.6 %

Procedure:
N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (1.6 g, 2.70 mmol) was dissolved in EtOH (30 mL) and 4N HCl (1 mL) added and heated to 50° C. overnight. Additional 4N HCl was added (1 mL) and heated for 4 hours. The reaction was cooled to ambient temperature, partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (10% methanol in EtOH) to afford (1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol hydrochloride (0.957 mg, 1.74 mmol, 64.6% yield) as a tan solid after HCl salt formation. Mass Spectrum (apci) m/z=513.1 (M+H−HCl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19]1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)(=[O:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Nc1ncnc2c1cnn2-c1cccc(NS(=O)(=O)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.0 eq, 0.17 mmol), 3-thiophenesulphonylchloride (31 mg, 1.0 eq, 0.17 mmol) and diisopropylethylamine (30 μl, 1.0 eq, 0.17 mmol) were added to DMF (1 ml) and the mixture was stirred for 18 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (13 mg, 0.03 mmol, 20%). LCMS: [M+H]+=373, Rt=1.60 min, 100% purity.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:19])[CH2:6]1)C.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]2[N:32]=[CH:4][C:5]3[CH2:6][C:7](=[O:19])[NH:8][C:9]4[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:10]=4[C:11]=3[N:31]=2)=[CH:27][CH:28]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(=CN(C)C)CC(=O)N2
Reactant: COc1ccc(CC(=N)N)cc1
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(C)c(C)cc2NC(=O)C3)cc1
Yield: 79 %

Procedure:
Analogous to Scheme 1,from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 79%.