Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:21])[N:10]=[N:11][C:12]=2[C:13]2[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:15]2[CH:14]=[C:13]([C:12]3[N:11]=[N:10][C:9]([NH2:21])=[N:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:18]=[C:17]([CH3:19])[N:16]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: C1CNC1
Reactant: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(Cl)n1
Product: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(N2CCC2)n1

Procedure:
6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine was prepared from 5-phenyl-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100 mg, 0.34 mmol) and azetidine (96 mg, 0.11 ml, 1.69 mmol) according to the general procedure for Preparation 4a.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]=[CH:22][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccccc2)ncc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cnc(Nc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a room temperature solution of 4-amino-2-phenylamino-pyrimidine-5-carboxaldehyde (2.89 g, 13.50 mmol) in 120 mL of tetrahydrofuran was added (carbethoxymethylene)triphenylphosphorane (11.00 g, 31.60 mmol). The reaction mixture was heated at reflux for 9 hours then stirred at room temperature overnight. The solution was concentrated in vacuo and treated with ethyl acetate and hexane to give a yellow solid. The solid was collected by filtration and purified by flash chromatography to give 1.55 g (40%) of ethyl 3-(4-amino-2-phenylamino-pyrimidin-5-yl)acrylate, mp 190-192° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@H:14]([OH:28])[C@@H:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:16]1)[CH2:11][CH2:10]3.[C:29]1([C:39]([N:41]2[CH2:48][CH2:47][CH2:46][C@H:42]2[C:43]([OH:45])=O)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:28][C@@H:14]1[C@@H:15]([N:22]2[CH2:23][CH2:24][N:25]([C:43]([C@@H:42]3[CH2:46][CH2:47][CH2:48][N:41]3[C:39]([C:29]3[CH:30]=[CH:31][C:32]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:38]=3)=[O:40])=[O:45])[CH2:26][CH2:27]2)[CH2:16][C@@:17]2([CH3:18])[CH:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)[C@@H](N5CCNCC5)C[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)[C@@H](N5CCN(C(=O)[C@@H]6CCCN6C(=O)c6ccc7ccccc7c6)CC5)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a solution of compound 36 (90 mg, 0.23 mmol) in anhydrous DMF (5 mL) at room temperature under an atmosphere of argon were added carboxylic acid 20 (68 mg, 0.25 mmol), PyBOP (132 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and DIPEA (128 μL, 0.74 mmol). The solution was subsequently stirred overnight at room temperature. The resulting solution was then poured into water and extracted with EtOAc (2×30 mL), washed with brine, dried with MgSO4 and evaporated to dryness. Purification by two successive flash chromatography procedures using (DCM/MeOH: 95:5) and (Hexanes/Acetone: 1:1) respectively and trituration with diethyl ether yielded 35 mg (23%) of compound 37. 1H NMR (CDCl3) δ: 0.73 (s, 18-CH3), 0.84 (s, 19-CH3), 0.65-2.25 (residual CH and CH2), 2.40-2.75 (broad m, 2×CH2N and 2α-CH), 3.19 (t, J=8.3 Hz, 17α-CH), 3.32 (s, OCH3), 3.45-3.95 (broad m, 2×CH2NCO, CH2N of proline and 3β-CH), 5.14 (t, J=7.6 Hz, NCHCO of proline), 7.52 (m, 2×CH of naphthalene), 7.67 (d, J=8.4 Hz, CH of naphthalene), 7.85 (m, 3×CH of naphthalene), 8.09 (s, CH of naphthalene). 13C NMR (CDCl3) δ: 11.7, 17.1, 21.0, 23.2, 27.6, 28.1, 29.4, 33.0, 35.2, 35.8, 38.4, 43.0, 48.0, 49.0, 50.3, 51.1, 55.7, 56.0, 56.2, 57.8, 59.3, 63.6, 63.8, 64.1, 64.7, 65.0, 66.9, 90.7, 126.6, 127.2, 127.4, 127.7, 127.8, 128.0, 128.6, 132.5, 133.6, 133.9, 169.5, 170.4 HRMS: calcd for C40H55N3O4: 642.4265, found [M+H]+ 642.4274.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH2:9])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>CC[O-].[Na+]>[NH2:11][C:10]1[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:7](=[O:8])[NH:9][C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(C)CNC(N)=O
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)(C)Cn1c(N)cc(=O)[nH]c1=O

Procedure:
N-neopentylurea (13.0 g, 0.1 mol) and ethyl cyanoacetate (10 ml) were heated in 4N NaOEt (100 ml) for 4 hours under reflux. The reaction mixture was evaporated to dryness, the residue treated with water (100 ml) and then acidified with AcOH to pH 4–5 to form a colorless precipitate. Yield: 11.2 g (59%).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[CH:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:8]1([CH2:7][C:6]([OH:17])=[O:5])[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)Cn1ccc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1ccc2cnccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 150.2 %

Procedure:
To a solution of pyrrolo[3,2-c]pyridin-1-yl-acetic acid tert-butyl ester (0.44 g, 1.89 mmol) in CH2Cl2 (10 mL) at 0° C. is added trifluoroacetic acid (1 mL). After 15 minutes, the solution is allowed to warm to room temperature and stirred for 18 hours. The reaction mixture is concentrated in vacuo and then azeotroped with toluene to give 0.5 g of the title compound as a residue (wet with excess TFA) which is used as is in the subsequent step
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[N:32]1>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([NH:40][C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[NH:31][N:32]=[CH:33]2)=[O:19]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2cccc(F)c2F)CC(=O)N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2cccc(F)c2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
The product from Example 70, Step 2 (80 mg, 0.30 mmol) was dissolved in CH2Cl2 (4 mL) under Argon. DMF (20 μL) was added, followed by oxalyl chloride (27 μL, 0.30 mmol). This mixture was stirred at rt for 30 min, then the resultant yellow solution was added to a solution of 1H-indazol-5-amine (44 mg, 0.33 mmol) in pyridine (3 mL) at −15° C. under Ar. After stirring at −15° C. for 15 min, the reaction mixture was allowed to warm to rt over 1 h. The mixture was poured into EtOAc (50 mL), washed sequentially with aq. NH4Cl (20 mL), NaOH (10 mL, 2.5 N), HCl (10 mL, 1.0 N) and then brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was triturated with 10% ethyl acetate/10% ether/80% hexanes to afford the title compound (56 mg, 49%). MS (ES+) m/e 383 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[S:43](Cl)(=[O:45])=[O:44]>C1COCC1>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[S:43]([NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:6]=1)(=[O:45])=[O:44]
Reactant: Nc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
(Some starting materials may be obtained from Alfa Aesar, Ward Hills, Mass.) To a flame-dry 50 mL rb flask was added 2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-amine (0.07 g, 0.2 mmol) and THF (8 mL). The reaction mixture was cooled to 0° C. followed by adding sodium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (0.4 mL, 0.4 mmol). After the addition, it was continued to stir at 0° C. under N2. After 30 min, 2,6-dichlorobenzene-1-sulfonyl chloride (0.07 g, 0.3 mmol) was added into the reaction mixture. After the addition, it was continued to stir at 0° C. then slowly warmed up to rt overnight. The reaction was quenched with water. The solvent was concentrated. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with DCM:EtOAc:MeOH=70%:26%:4% as the solvent system to afford the desired product as light yellow solid (63.0 mg). MS (ESI pos. ion) m/z: calc'd for C24H19Cl3N4O3S: 548.1; found: 549.4 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.21-3.38 (m, 4 H) 3.93-4.11 (m, 4 H) 6.94 (d, J=4.97 Hz, 1 H) 7.33-7.44 (m, 1 H) 7.45-7.55 (m, 2 H) 7.85 (dd, J=8.77, 2.05 Hz, 1 H) 8.18 (d, J=8.77 Hz, 1 H) 8.25 (d, J=1.90 Hz, 1 H) 8.39-8.50 (m, 2 H) 8.81 (d, J=4.97 Hz, 1 H).
Reaction SMILES: C[O-].[Na+].Cl.Cl.[CH2:6]([NH:13][NH2:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]([CH2:17][C:18]([C:20]1[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=1)=O)#[N:16].O>C(O)C>[NH2:16][C:15]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=[C:18]([C:20]2[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH:17]=1
Reactant: N#CCC(=O)c1ccc(CO)o1
Reactant: NNCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1

Procedure:
44.1 g (817 mmol) of sodium methoxide is added with stirring to a solution of 79.5 g (408 mmol) of benzylhydrazine dihydrochloride in 1.3 l of ethanol. After 15 min 67.4 g (408 mmol) of 2-cyanomethylcarbonyl-5-hydroxymethylfuran are added and the mixture is stirred under reflux for 3 hours. After cooling, 1 l of water is added, the ethanol part is evaporated in vacuo and the precipitated crystals are filtered off with suction. After washing, with water and then with ether, the precipitate is dried over P2O5, 91 g(83% of theory) of product having an m.p. of 163° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.IC.[C:25]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=3)[N:10]([CH3:25])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(=O)n(-c3cccc(Br)c3C)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.7 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione (440 mg, 1.22 mmol) in THF (30 mL) was treated with iodomethane (303 mg, 2.13 mmol) and Cs2CO3 (869 mg, 2.67 mmol) at room temperature. The mixture was stirred at room temperature overnight, then was filtered and concentrated. The residue was dissolved in DCM and washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated to give 3-(3-bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione (502 mg), used without further purification. Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.21 (d, J=8.8 Hz, 1H), 7.67 (dd, J=7.9, 1.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.17-7.13 (m, 1H), 6.88 (dd, J=8.8, 2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.64 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C@H:6]([CH2:14][OH:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].CO>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl>[C:8]1([CH2:7][C@H:6]2[CH2:14][O:15][C:1](=[O:2])[NH:5]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1N[C@@H](Cc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The following experiment was done in a fume hood. Phosgene ("ca" 150 mL) in toluene (200 mL) was added dropwise over 1 h to a mechanically stirred mixture of (S)-phenylalaninol, prepared as described above, (79.1 g, 0.52 mol), toluene (900 mL), and aqueous sodium hydroxide (12.5% w/v, 1300 mL) that was cooled in an ice-bath. The reaction was monitored by TLC (silica, 1:19 methanol--chloroform) and found to be complete 30 min after the end of the addition. The cooling-bath was removed and the mixture was stirred overnight. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The extracts and the toluene layer were combined, dried (MgSO4), and evaporated to afford a solid residue. This material was dissolved in the minimum volume of boiling ethyl acetate, and hexane was added until the solution just became turbid. The solution was allowed to cool to room temperature and was then kept overnight in a refrigerator. Filtration afforded 19 as large, colorless crystals (80 g, 86%): mp 87°-89° C. (lit.2 87°-88.5° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)[CH2:29][CH2:28]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN1CCN(C[C@H]2CC[C@H](N)CC2)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCN(C)CC2)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-4-[(4-methylpiperazin-1-yl)methyl]cyclohexanamine (330 mg, 1.6 mmol) to afford the desired product (32 mg, 7%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.93-10.89 (m, 1H), 8.95 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.09-4.90 (m, 1H), 3.31 (br s, 4H), 2.90 (br s, 4H), 2.75 (s, 3H), 2.68 (s, 3H), 2.43-2.24 (m, 4H), 1.99-1.87 (m, 2H), 1.62-1.46 (m, 1H), 1.47-1.07 (m, 4H); ESI MS m/z 416 [M+H]+
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC1CC(=O)c2sc(Br)nc2C1
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O)c2sc(Br)nc2c1
Temperature: 90 °C
Yield: 71 %

Procedure:
To a solution of 26 (7.38 g, 30.0 mmol) in CCl4 (90 mL) was added NBS (5.61 g, 31.5 mmol) and dibenzoyl peroxide (727 mg, 3.0 mmol). The reaction was heated at 90° C. in a sealed reaction vessel for about 4 h. Then DBU (6.73 mL, 45.0 mmol) in CH2Cl2 (15 mL) was added. The mixture was heated a reflux for 30 min, then a 1 M HCl solution was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with a brine solution. The organic layer was then dried, filtered, and concentrated in vacuo. The crude product was adsorbed on ˜30 g of silica then run through a plug of silica with 40% EtOAc/hexanes to give 5.2 g of 27. 1H-NMR: 400 MHz, (CD3OH) δ: 7.25 (s, 1H), 6.69 (s, 1H), 2.40 (s, 3H). LCMS-ESI+: calc'd for C8H7BrNOS: 243.9 (M+H+); Found: 244.1 (M+H+).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][C:14](=[O:16])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OC(=O)CC(=O)C1C=CC(OC)=CC=1)C.O.NN>>[CH3:10][O:9][C:8]1[CH:3]=[CH:4][C:5]([C:11]2[CH2:15][C:14](=[O:16])[NH:13][N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1OC
Agent: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2)cc1
Yield: 67 %

Procedure:
The starting material was prepared using an analogous procedure to that described for the synthesis of 3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one in Example 9. Ethyl-4-methoxybenzoylacetate (1 g, 4.5 mmol) was reacted with hydrazine hydrate (218 μl, 4.5 mmol) to give 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (570 mg, 67%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:14])[CH2:6]1.[CH3:15]I.O>CCCCCC.C1COCC1.[Cl-].[Na+].O>[CH3:15][O:3][CH2:4][C:5]1[CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:14])[CH:6]=1
Reactant: O=C1CC(CO)Cc2sccc21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC1=CC(=O)c2ccsc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.2 g, 5 mmol), was washed with hexane and then suspended in THF (6 mL) under a nitrogen atmosphere at 0° C. 6-(Hydroxymethyl)-6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.745 g, 4.1 mmol) was dissolved in THF (4 mL) and added drop-wise to the sodium hydride suspension. After 10 min methyl iodide (0.71 g, 0.31 mL, 5 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 3 hr. Water and saturated brine solution (2 mL, 1:1) were added and the product was extracted into dichloromethane (×3). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The crude residue was purified on silica gel using a gradient elution of 0-50% ethyl acetate in iso-hexane to afford the title compound (0.109 g, 34%).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@@H:6]([OH:18])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[CH3:3].Cl.C(O)(=O)C(C1C=CC=CC=1)O>>[CH3:3][CH:2]([NH:4][CH2:5][CH:6]([OH:18])[C:7]1[CH:8]=[CH:9][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[CH3:1]
Reactant: CC(C)NC[C@@H](O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C(O)C(O)c1ccccc1
Product: CC(C)NCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In addition, using chemical method as described by Le Garrec (1987), enriched d-sotalol hydrochloride and l-sotalol hydrochloride were prepared using mandelic acid and subjected to conversion to the base form, chiral separation and reconversion to hydrochloride salt was carried out. The details of these procedures are given below:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)on2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cc(-c3ccc(Cl)cc3)on2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of methyl 4-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate (1.35 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (20 ml) and methanol (10 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (10 ml) was added. The crystals were collected by filtration, and recrystallized from tetrahydrofuran-hexane to give 4-[5-(4-chlorophenyl)-3-isoxazolyl]benzoic acid (1.19 g, yield 92%) as colorless crystals. melting point: >300° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>C1COCC1>[CH2:1]([O:8][N:9]1[C:10](=[O:28])[C:11]2[C:12](=[CH:13][C:14]([F:18])=[C:15]([F:17])[CH:16]=2)[N:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C:29]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 68.1 %

Procedure:
N-benzyloxy-2-(2,4-difluoroanilino)-4,5-difluoro-benzamide (Example I-4, 5.66 g, 15 mmol) and carbonyldiimidazole (2.83 g, 17 mmol) were combined in 300 mL of THF and heated to reflux for 30 hours. The solution was cooled, concentrated, and redissolved in chloroform. The solution was washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 4.25 g of a solid which was purified by column chromatography (silica gel, CHCl3/MeOH, 98:2) to give 2.0 g of the title compound as a solid.
Reaction SMILES: CO.[F:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][C:9]2[CH:18]=[C:17]([CH:19]=[CH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C=CCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CCCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixed solution of methanol 8 mL and ethyl acetate 2 mL of the obtained methyl 2-(4-fluoroanilino)-4-(3-phenyl-1-propenyl)benzoate, 5% palladium-carbon 0.060 g was added, and it was stirred under hydrogen atmosphere at room temperature for 1 hour. Insoluble matter of the reaction mixture was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give methyl 2-(4-fluoroanilino)-4-(3-phenylpropyl)benzoate 0.10 g of colorless oil.
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:19][OH:20])[C:13]=2[CH:12]=[CH:11]1.C1C(=O)N([Cl:29])C(=O)C1>CN(C=O)C>[CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:19][OH:20])[C:13]=2[C:12]([Cl:29])=[CH:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(NO)ncnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(Cl)c2c(NO)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Nucleoside 117 (0.1 mmol) is dissolved in DMF (0.5 mL) and cooled to 0° C. NCS (0.1 mmol) dissolved in DMF (0.5 mL) is then added dropwise and the reaction stirred for 30 minutes at 0° C. and 30 minutes at room temperature. The reaction is quenched with methanol (5 mL) and then concentrated. Column chromatography (SiO2) with MeOH/DCM affords 123.