Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[OH:33][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(O)c3ccccn3)cc1-2
Yield: 17 %

Procedure:
10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol via General Procedure E to yield 14 mg (17%) of (±)-10-[3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:22])=[C:8]([F:21])[CH:9]=2)[N:4]=1.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:22])=[C:8]([F:21])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: O=c1c2cc(F)c(F)cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(F)c(F)cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 53.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2q (200 mg, 0.586 mmol), 6-mercaptopurine monohydrate (110 mg, 0.645 mmol), K2CO3 (89 mg, 0.645 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 143 mg of a pale yellow crystalline solid (53%), mp 207.8° C. (discolors; sweats at 136(C). 1H NMR (DMSO-d6) δ: 13.57 (br s, 1H); 8.49 (s, 1H); 8.46 (s, 1H); 8.11 (t, J=9.4 Hz, 1H); 7.88 (dd, J=7.3, 11 Hz, 1H); 7.77 (dd, J=1.7, 7.3 Hz, 1H); 7.67 (d, J=7.4 Hz, 1H); 7.42-7.55 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.5 (d, J=2.5 Hz), 154.6 (dd, J=14, 255 Hz), 154.0 (d, J=1.5 Hz), 151.5, 149.3 (dd, J=14, 250 Hz), 145.1 (d, J=12 Hz), 143.9, 133.9, 132.1, 131.8, 131.4, 130.5, 128.9, 118.0 (d, J=4.9 Hz), 115.8 (d, J=18 Hz), 114.6 (d, J=20 Hz), 32.0. MS (ES): m/z 457.0 (M+). Anal. calcd. for C20H11ClF2N6OS: C, 52.58; H, 2.43; Cl, 7.76; N, 18.40; S, 7.02. Found: C, 51.81; H, 2.37; Cl, 7.49; N, 18.04; S, 7.55.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18](O)=[O:19])[C:6]=2[CH:21]=1.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN>CN(C=O)C>[Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:33][CH3:31])=[O:19])[C:6]=2[CH:21]=1
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3F)c(C(=O)O)c2cc1Br
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (440 mg, 0.99 mmol), HOBT (199 mg, 1.48 mmol) and EDCI (283 mg, 1.48 mmol) in dry DMF (10 mL) was stirred at 25° C. After 2 hours, Et3N (299 mg, 2.96 mmol) and MeNH2 (200 mg, 2.96 mmol) was added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H2O (20 mL) and extract with EtOAc (40 mL*3), dried over Na2SO4, After concentrated, the resulting residue was purified using column chromatography (dichloromethane:EtOAc=2:1) to provide 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 88%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1H), 8.19 (d, J=3.6 Hz, 1H), 7.97 (s, 1H), 7.80˜7.86 (m, 1H), 7.73 (s, 1H), 7.44˜7.50 (m, 1H), 7.27˜7.31 (m, 1H), 3.02 (s, 3H), 2.75 (d, J=4.8 Hz, 3H). MS (M+H)+: 459/461.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH2:27][NH:26][CH:25]2[C:29]([NH2:31])=[O:30])[CH2:23]1.Cl.C1C2(CC(C(N)=O)NC2)C1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:24]4([CH2:22][CH2:23]4)[CH:25]3[C:29]([NH2:31])=[O:30])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C1NCCC12CC2
Agent: Cl
Agent: NC(=O)C1CC2(CC2)CN1
Product: NC(=O)C1N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CCC12CC2

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 80 mg, 281 μmol) was reacted with a mixture of 5-azaspiro[2.4]heptane-4-carboxamide hydrochloride and 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 151 d, 59.7 mg, 338 μmol) to obtain the title compound after preparative chiral HPLC (22 mg, 19%) as off-white solid, MS (ESI): m/e=407.3 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1.C(O)(C(F)(F)F)=O.[I:24]N1C(=O)CCC1=O.[NH4+].[OH-]>C(O)(=O)C>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:24])[C:8](=[O:11])[NH:9][CH:10]=1
Reactant: O=c1ccc(Cc2ccc(F)cc2F)c[nH]1
Reactant: O=C1CCC(=O)N1I
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=c1[nH]cc(Cc2ccc(F)cc2F)cc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2,4-difluorobenzyl)pyridin-2(1H)-one 3 (1.89 g, 8.5 mmol) in acetic acid (34 ml) was added TFA (2.2 ml), followed by N-iodosuccinimide (2.02 g, 8.5 mmol). The red homogeneous solution was allowed to stir overnight at room temperature, poured onto ice and neutralized with cone. NH4OH. The solid was collected by filtration, rinsed with water, treated with methanol/dichloromethane, dried over sodium sulfate, and evaporated. The resulting brown solid was purified by flash column chromatography on silica gel (hexanes:ethyl acetate, 50:50). Yield 2.57 g (87%). 1H NMR (CDCl3, 500 MHz): δ 13.20 (s, 1H), 7.98 (d, 1H, J=2.2 Hz), 7.26-6.81 (m, 4H), 3.70 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 162.5, 161.9, 160.5, 151.9, 133.5, 131.2, 121.8, 120.0, 111.6, 104.3, 91.6, 29.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClS(O)(=O)=O.Cl>O>[CH:6]1[C:5]([S:8]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)(=[O:10])=[O:11])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Clc1ccccc1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 60 %

Procedure:
A 211 g (1.1 moles) quantity of 4-chlorobenzenesulfonic acid was added to 112 g (1 mole) of chlorobenzene and the mixture was cooled with water while 123 g (1.1 moles) of chlorosulfonic acid was added to the mixture at about 10° to about 20° C. over a period of 1 hour. After the addition, the reaction mixture was stirred for 3 hours while being maintained at 20° to 30° C. The hydrochloric acid gas evolved during the reaction was continuously removed from the reaction system. After the termination of the reaction, about 400 ml of water was added to the reaction mixture and 11.2 g (0.1 mole) of the unreacted chlorobenzene was recovered by distillation. The separation of the precipitate formed gave 77 g of 4,4'-dichlorodiphenylsulfone in a yield of 60% (based on the amount of the aromatic hydrocarbon as consumed, the same hereinafter). M.P. 148.5° to 149.5° C. Purity of 99.8% (according to liquid chromatography, the same hereinafter).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]([CH3:10])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CNCCO
Product: CN(CCO)c1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and N-methylethanolamine.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:10]1[C:9]2[N:8]=[C:7]([CH2:19][CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:22])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)NC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)NC

Procedure:
N-Methyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (4.7 g, 13 mmol) was treated with mCPBA (6.58 g, 38.2 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (3.27 g, 17.2 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part D of Example 8 to provide 0.674 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide as a tan powder, mp 177-178° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[O:22])[N:4]=1)#[N:2]
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H]2CCCC[C@H]2C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), cis-2-amino-cyclohexanecarboxylic acid (67 mg, 0.47 mmol, Acros) and sodium methoxide (20 mg, 0.37 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes with 0.5% formic acid) to give the title compound in 34 mg. MS: (−) m/z 429.99 (M−1).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C(N(C(C)C)CC)(C)C.Cl.[C:34]1([C:40]2([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C@@H:48]3[C@@H:44]([CH2:45][NH:46][CH2:47]3)[C@@:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])([OH:49])[CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN=C=NCC>ClCCl>[C:58]1([C:40]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:48]3[C@@H:44]([CH2:45][N:46]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:47]3)[C@@:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])([OH:49])[CH2:42][CH2:41]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
0.025 g of 1-hydroxybenzotriazole, 0.38 g of (S)-2-(2-methoxyphenyl)propionic acid and 0.32 cm3 of diisopropylethylamine are added to a suspension of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry dichloromethane, this solution is then cooled to +5° C. and a suspension of 0.43 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in 10 cm3 of dry dichloromethane is rapidly added. The reaction mixture is stirred for 2 hours at +5° C. and for 2 hours at room temperature, washed with 20 cm3 of water, then washed with 20 cm3 of a saturated aqueous sodium chloride solution (twice), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 25 cm3 fractions. Fractions 9 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile and diisopropyl ether. There is obtained 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of white crystals melting at 244° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.ClCCl>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccccn4)cc3)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
To a solution of (E)-N-[4-(2-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (350 mg) in tetrahydrofuran (10 ml) and dichloromethane (30 ml) was added 3-chloro-perbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol/ethyl acetate=1:1) concentrated to give crystals, which were recrystallized from ethanol-chloroform to give (E)-N-[4-(1-oxidopyridin-2-yl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 189) (188 mg) as pale yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.O.O.O.[C:18]([O-])(=[O:20])[CH3:19].[Na+].C(OC(=O)C)(=O)C>O>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18](=[O:20])[CH3:19])[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-2-(1-piperazinyl)-pyrazine hydrochloride (15 g, 0.064 mole) is added to a solution of 20 g of sodium acetate trihydrate (0.147 mole) in 250 ml ice water. The vigorously stirred mixture is treated with 15 ml acetic anhydride followed by 100 ml water. The mixture is stirred 3 hours while warming to room temperature and the product, which separates as an oil, is extracted with toluene. The toluene extract is washed with water and concentrated in vacuo to give a crude product which is recrystallized twice from n-butylchloride to give the title compound, mp 106°-107.5° C.
Reaction SMILES: O[C:2](C)(C#C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1.[H-].[Na+].C1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1)#[CH:2]
Reactant: C#CC(C)(O)Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine (495 mg, 1.5 mmol) was dissolved in toluene (30 mL) and catalytic sodium hydride (10 mg) was added. The solution was heated until several milliliters of toluene-acetone mixture was removed by distillation. The mixture was cooled to 25° C. and water (20 mL) and ethyl acetate (40 mL) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×40 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:3) as eluant to afford 5-ethynyl-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine as an oil (250 mg, 61%). LRMS (EI) m/e 217 (M+ +H --isobutylene), 216 (M+ --isobutylene); 1H NMR (CDCl3, 300 MHz): δ 8.59 (b-s, 1H), 8.42 (d, J=1.5 Hz, 1H), 7.59 (b-s, 1H), 4.94 (b-m, 0.5H), 4.77 (b-m, 0.5H), 3.64 (b-m, 2H), 3.21 (s, 1H), 2.39 (m, 1H), 1.75-2.0 (b-m, 3H), 1.46 (s, 3H), 1.21 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[N:27]=[N:28][CH:9]=2)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc(C(=N)NN)cc1
Agent: I
Product: COc1ccc(-c2nncc(-c3ccc(F)c(C(F)(F)F)c3)n2)cc1

Procedure:
(4-Fluoro-3-trifluoromethylphenyl)oxoacetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (2.37 g, 8.08 mmol) using the method described in Example 1 to give 5-(4-fluoro-3-trifluoromethylphenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine as a yellow solid (1.13 g): δH (400 MHz, CDCl3) 3.92 (3H, s), 7.06-7.10 (2H, m), 7.44 (1H, t, J 9.2 Hz), 8.44-8.49 (1H, m), 8.56 (1H, dd, J 2.0, 6.7 Hz), 8.58-8.62 (2H, m), 9.54 (1H, s); m/z (ES+) 350.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=1>>[NH2:15][C:16]1[C:17]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH2:32])=[O:33])=[CH:27][CH:26]=2)=[CH:18][C:19]([C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH:12]3[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[CH:20][N:21]=1
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)cc1
Reactant: NC(=O)c1ccc(-c2cc(B(O)O)cnc2N)cc1
Product: NC(=O)c1ccc(-c2cc(-c3ccc(S(=O)(=O)NC4CC4)cc3)cnc2N)cc1
Yield: 47.3 %

Procedure:
General method B was applied to 4-bromo-N-cyclopropylbenzenesulfonamide (41 mg, 0.15 mmol), 6-amino-5-(4-carbamoylphenyl)pyridin-3-ylboronic acid (53 mg, 0.15 mmol), to give 4-(2-amino-5-(4-(N-cyclopropylsulfamoyl)phenyl)pyridin-3-yl)benzamide as a white solid (29 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, J=2.3 Hz, 1H), 8.03 (br. s., 1H), 7.98 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 7.87 (d, J=2.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.76 (d, J=1.5 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.37 (br. s., 1H), 6.06 (br. s., 2H), 2.06-2.13 (m, 1H), 0.42-0.50 (m, 2H), 0.35-0.42 (m, 2H); MS (EI) m/z: 409 [M+H]+.
Reaction SMILES: [S:1](=[C:4]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[CH2:5][CH2:6][CH3:7])(=[O:3])=[O:2].[CH3:14]I>>[CH3:14][N:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:4](=[S:1](=[O:3])=[O:2])[CH2:5][CH2:6][CH3:7])[CH2:13]1
Reactant: CCCC(c1cnccn1)=S(=O)=O
Reactant: CI
Product: CCCC(C1=NC=CN(C)C1)=S(=O)=O

Procedure:
3.6 g of 2-(1-sulfonylbutyl)pyrazine (1100) was added to a solution of 10 ml methyl iodide/25 ml methanol and the mixture refluxed for 4 days. It was then concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying gave 3.2 g of product (1200) which was recrystallized from propanol/water, m.p. 293°-5° (dec). UV H2O max: 206 (3.87), 283 (3.90). 1H NMR: 9.41, D, T (H6); 9.11, S (H2); 8.94, D (H5); 4.63-4.58, M (CHSO3-); 4.52, S (NCH3); 2.31, M (CH2CHSO3-); 1.27, M (CH2CH3); 0.89, T (CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Li]CCCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=[O:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]([OH:32])[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 1-bromo-4-(trifluoromethoxy)benzene (1.88 g, 7.80 mmol) in THF (16 mL) at −78° C. was added n-BuLi (1.9M in hexanes, 4.1 mL, 7.8 mmol), and the solution was stirred at −78° C. for 30 minutes. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 7.03 mmol) in THF (2 mL) was added dropwise, and the mixture was stirred at −78° C. for 45 minutes then allowed to warm to room temperature over 1 h. Work-up and purification gave 4-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals (1.75 g, 66%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)o1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)o1
Temperature: 25 °C

Procedure:
To a stirred suspension of 8.43 g (44.14 mmol) of 5-bromo-2-furoic acid in 100 ml absolute ethanol was added 4 ml of thionyl chloride. This mixture was stirred at reflux for 3 hours and at room temperature for 18 hours. The solvent was removed in vacuo, the residual oil treated with 100 ml water and extracted with 3×75 ml ether. The combined ether extracts were washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue kugelrohr distilled (60° C.; 0.4 mm) to give the captioned compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl[CH2:8][CH:9]([OH:15])[CH2:10][S:11]([OH:14])(=[O:13])=[O:12].[Na]>O1CCOCC1.O>[OH:15][CH:9]([CH2:8][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:10][S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)CC(O)CCl
Reactant: CC(C)CCN
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCNCC(O)CS(=O)(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a 80° C. solution of isoamylamine (2.0 g, 22.9 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added via syringe pump (1 h addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (3.04 g, 15.3 mmol) in 1,4-dioxane (9.5 mL) and water (0.5 mL). The solution was stirred overnight at 80° C. The solvent was evaporated. The product was passed through an ion exchange column (Dowex 50×8, 100 g, solvent: water). It was recrystallized in absolute EtOH and lyophilized. Yield: 27%. 1H NMR (H2O, 500 MHz) δ ppm 4.24 (m, 1H), 3.22 (m, 1H), 3.02 (m, 5H), 1.49 (m, 3H), 0.79 (d, 3H, J=6.3 Hz). 13C(H2O, 125 MHz) δ ppm 63.54, 54.89, 51.53, 46.48, 34.12, 25.46, 21.56, 21.46. ES-MS 226 (M+1).